The study, published in Nature on 9 September 2026, was co-led by the Spanish National Cancer Research Centre within the Pan Prostate Cancer Group, an international consortium that has assembled what the researchers described as the world’s largest collection of prostate cancer genomes. It examined 959 tumour samples donated by men in seven countries. All samples were processed in the same way and paired with medical follow-up over a median of seven years. The investigators also checked the findings in a second, independent set of tumours, although the research release did not provide details about the size or composition of that set.

Rather than treating each form of genomic alteration as a separate phenomenon, the team integrated four classes of DNA damage: single-letter changes, short stretches of DNA gained or lost, large structural rearrangements, and large losses or gains of genetic material. These patterns are known as mutational signatures, which provide clues about the biological processes that produced them. Previous studies had generally examined one type at a time. By analysing all four together, the investigators identified eight recurring processes related mainly to hormone signalling, defective DNA copying, faulty DNA repair and ageing. Most prostate cancers were therefore not characterized by a single isolated defect but by several active processes at once.

The balance among those processes differed between patients. Geoff Macintyre, head of the Computational Oncology Group at the CNIO and one of the study’s supervisors, said that the balance of processes operating within a tumour is associated with how likely the cancer is to spread. The release quoted him saying that reading one type of DNA damage at a time is like transcribing a symphony from the cello part alone: it reveals the tempo but not the whole work. In the combined analysis, the eight processes emerged as overlapping biological states rather than sealed compartments that could cleanly sort patients into distinct groups.

One prominent result concerned a process that, when it was the most active in a tumour, was associated with a greater likelihood of metastatic spread. The association remained after the researchers accounted for patient age, tumour stage and the grade assigned by a pathologist examining the tumour under a microscope. This linked the relative prominence of a genomic process with disease behaviour beyond those conventional factors. Because the study was observational, however, it did not establish that the process directly causes metastasis or show that measuring it would improve predictions in routine clinical practice.

The researchers also linked one active process to a small group of 25 patients who appeared to respond better to a specific type of therapy. This finding came from a post hoc subgroup analysis rather than a trial designed to test whether the process should guide treatment selection. The small number of participants and the lack of a prospective comparison mean that the observation remains exploratory. It does not yet establish which therapy should be selected for an individual patient, but it identifies a hypothesis that would need evaluation in larger, independently designed clinical studies.

Another striking feature was the scarcity of signatures associated with external carcinogens. The investigators searched for recognizable DNA traces of tobacco, ultraviolet radiation and other environmental agents, comparable to those readily detected in lung or skin cancers, but found practically none across almost 1,000 genomes. Barbara Hernando, a researcher at the CNIO and one of the study’s four joint first authors, said the team was surprised by the scale of damage arising from within the cell. The absence of these signatures did not mean that environmental exposures or lifestyle were irrelevant to prostate cancer. Hernando said diet, weight and inflammation can influence whether the disease develops without leaving a detectable trace in the DNA.

The analysis nevertheless brings the prospect of prognostic biomarkers closer. Macintyre said the findings must first be confirmed in other patient groups. A candidate measurement would then need to become a test that produces the same answer every time, be evaluated in men making actual treatment decisions and be shown to help them. Joachim Weischenfeldt, a professor at the Biotech Research and Innovation Centre of the University of Copenhagen and Rigshospitalet and another study supervisor, said the work was not expected to change treatment immediately. These requirements extend beyond the observational analysis and the exploratory treatment-response finding reported here.

Weischenfeldt described the contribution as a map of the biological processes that drive prostate cancer and emphasized that it uses DNA sequencing already performed by several health systems. The proposed approach is to read existing data differently rather than build a new test from scratch. The practical promise lies in using the combinations and relative strengths of mutational signatures to represent the multiple processes operating within a tumour more fully. The present evidence comes from human tissue samples, however, and remains insufficient to support a clinical recommendation or a change in how prostate cancer is treated.

Subject of Research: Mutational processes associated with DNA damage and progression in human prostate cancer tumours

Article Title: Scientists reveal what damages the DNA in most prostate cancers

Article References: Scientists reveal what damages the DNA in most prostate cancers. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: prostate cancer, cancer genomics, mutational signatures, DNA damage, tumour heterogeneity, DNA repair, metastasis, computational oncology, prognostic biomarkers, personalized medicine, Scientists, reveal

Urinary cPU concentrations were quantified with liquid chromatography–tandem mass spectrometry, while expression of six nucleotide excision repair genes—XPB, XPC, XPD, XPF, ERCC1 and CSB—was measured in peripheral blood samples using quantitative reverse transcription PCR. The investigators described the study as an assessment of DNA-lesion levels and repair-gene expression in people with bipolar disorder, their unaffected siblings and healthy controls. The cPUs examined are tandem oxidative lesions that distort the DNA helix and impair replication and transcription.

The source study states that they are repaired primarily by the nucleotide excision repair pathway. Both the bipolar disorder and sibling groups had significantly elevated urinary cPU concentrations compared with healthy controls. R-cdA concentrations were highest in the sibling group.

These observations show that elevated lesion concentrations were present in the two groups sharing a family connection, rather than only among participants diagnosed with bipolar disorder. The group comparison did not establish whether the concentrations preceded illness, caused bipolar disorder or predicted future symptoms. Expression of four repair-related genes was increased in the sibling group: XPB, XPF, ERCC1 and CSB.

XPC expression was elevated in both the bipolar disorder and sibling groups relative to healthy controls. Other comparisons distinguished the sibling group from the bipolar disorder group. XPB, XPF and CSB expression was significantly higher in siblings than in participants with bipolar disorder, whereas XPD expression was increased in the bipolar disorder group compared with both the sibling and healthy-control groups.

The results therefore comprised elevated cPU concentrations in both family-linked groups and distinct patterns of repair-gene expression among bipolar disorder participants, unaffected siblings and controls. The authors interpreted the combined findings as support for prior evidence implicating oxidative DNA damage and repair mechanisms in bipolar disorder pathogenesis. They proposed that the cPU lesions and the differing expression patterns may be useful as additional molecular markers and may indicate a potential familial vulnerability associated with the development of bipolar disorder.

The study itself does not demonstrate that elevated lesions or altered gene expression cause the disorder, that either precedes its onset, or that either constitutes a clinical diagnostic test. The results instead identify measurable molecular differences in bipolar disorder and unaffected sibling groups that warrant further investigation as potential indicators of oxidative DNA damage and altered repair activity.

Subject of Research: Oxidative DNA lesions and nucleotide excision repair gene expression in bipolar disorder, unaffected siblings and healthy controls

Article Title: Cyclopurine DNA lesions and repair in individuals with bipolar disorder and their unaffected siblings

Article References: Arat Çelik, H. E., Tuna, G., Akşahin, İ. C., Yılmaz, S., Fettahoğlu, İ., Eslami Abriz, A., Gör, C., Çörekli, E., Kök Kendirlioğlu, B., Dal Bekar, N. E., Çelik, Ö. F., Yorguner, N., & Ceylan, D. (2026). Cyclopurine DNA lesions and repair in individuals with bipolar disorder and their unaffected siblings. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04519-z

Image Credits: AI Generated

DOI: 10.1038/s41398-026-04519-z

Keywords: bipolar disorder, oxidative DNA lesions, nucleotide excision repair, DNA repair, familial vulnerability, gene expression, R-cdA, mass spectrometry, peripheral blood, biomarkers, Cyclopurine, lesions

Investigators isolated nuclei from frozen parietal-cortex tissue and used fluorescence-activated cell sorting to enrich NeuN-positive neuronal populations. Two sorting rounds produced samples in which more than 70% of nuclei were tetraploid, although one Alzheimer’s sample was discarded because it did not meet that threshold. Researchers then extracted genomic DNA from 430 to 550 neuronal nuclei per sample and amplified it with PicoPLEX before preparing exome libraries for sequencing. The resulting reads were aligned to the human reference genome, and SNVs and INDELs were called with VarScan 2 and LoFreq. Variants were classified as germline or somatic primarily by allele frequency: a threshold of 0.25 separated the low-frequency population interpreted as somatic from the predominantly germline variants at higher frequencies.

The rise in mutations was highly specific to single-base changes. Overall, Alzheimer’s-derived tetraploid neurons contained 16% more mutations than diploid neurons from the same patients, with the difference attributable to a 17% increase in sSNVs. Somatic INDEL counts were similar in tetraploid Alzheimer’s neurons, diploid Alzheimer’s neurons and control neurons. A second analysis with LoFreq, which can identify variants occurring at frequencies as low as roughly 0.05% to 1%, again found significantly more sSNVs in tetraploid cells. Most were concentrated at allele frequencies of 0.005 to 0.03, with a pronounced peak at 0.01, whereas diploid neurons had a flatter distribution. In the broader analysis, the proportion of somatic variants rose by 45% in tetraploid neurons relative to control neurons.

Mutation type provided another striking clue. Tetraploid neurons were strongly enriched for thymine-to-cytosine transitions, written T>C, which are equivalent to adenine-to-guanine changes on the complementary DNA strand. This class accounted for roughly 64% of variants unique to tetraploid neurons, compared with about 37% of variants shared by diploid and tetraploid populations and 34% of variants unique to diploid neurons. Such transitions have been associated with oxidative DNA damage, including damage linked to lipid peroxidation. The T>C enrichment was also concentrated among variants below an allele frequency of 0.05, indicating that it was especially pronounced in the ultra-low-frequency population enriched in Alzheimer’s tetraploid cells.

The authors also compared the variant profiles with established single-base substitution signatures derived from large cancer-sequencing datasets. SBS123 made the largest contribution in most samples, but its relative share was higher in the tetraploid Alzheimer’s group, reaching 64% to 66% of fitted mutations, compared with 49% to 57% in controls and 52% to 59% in diploid Alzheimer’s neurons. The two tetraploid samples also shared a secondary combination of SBS116 and SBS5 that was not consistently present in the diploid groups. Cosine similarities between observed and reconstructed spectra ranged from 0.938 to 0.958. These analyses support a shift in the mixture of mutational processes associated with tetraploidy, rather than the appearance of a wholly tetraploid-specific signature.

Gene-level analysis showed that Alzheimer’s tetraploid neurons accumulated especially many sSNVs in pathways governing oxidative stress and DNA repair. Total SNVs increased by 38% in genes associated with antioxidant activity, 31% in genes involved in the response to reactive oxygen species, 29% in genes linked to hydrogen peroxide activity and 26% in genes associated with oxidative stress. Somatic variants in antioxidant and reactive-oxygen-response genes increased by 64% and 61%, respectively, both larger than the 45% genome-wide rise. Among DNA-repair genes, total SNVs increased by 31% and sSNVs by 64% in tetraploid cells. Base-excision, mismatch and nucleotide-excision repair genes showed significant sSNV increases, whereas double-strand-break-repair genes did not.

Not every disease-related category behaved as expected. Somatic variants also accumulated in genes associated with Parkinson’s disease, including a 64% increase over the genome-wide value, while sSNVs in Alzheimer’s risk genes rose by 59%. The pattern varied among individual genes, with significant increases in ABCA7, APOE, BIN1, CD33, EPHA1, MAPT, PSEN2, SMARCA4 and PLD3, but decreases in CD2AP and PSEN1. The study therefore found no simple, exclusive association between mutations in Alzheimer’s genes and the tetraploid state. A computational molecular pathogenicity analysis instead suggested that the mutations affecting genes in cancer and senescence pathways were more likely than random variants to be predicted to damage protein function.

That pathogenicity analysis used a score ranging from zero for the least pathogenic prediction to five for the most pathogenic and combined outputs from 12 computational tools. Cancer-related and senescence-related sSNVs had significantly steeper score distributions than generic genes, as did variants in several oxidative-stress and DNA-repair categories. Alzheimer’s and Parkinson’s risk genes did not show higher scores than control genes. These are computational predictions, not measurements of protein activity. The study did not perform functional assays, matched RNA sequencing or targeted validation of individual variants, so the data cannot establish that the mutations impaired DNA repair, altered gene expression or drove cell-cycle re-entry.

A central technical concern is that the neuronal DNA underwent whole-genome amplification before sequencing. PicoPLEX can introduce allelic imbalance, allelic or locus dropout and polymerase-derived errors, all of which may alter the frequencies used to distinguish somatic from germline variants. The distinct T>C spectrum in tetraploid-specific variants and its resemblance to independently established mutational signatures argue against a uniform amplification bias fully explaining the population-level pattern. They do not, however, rule out stochastic errors affecting individual low-frequency calls. The investigators also used a non-parametric bootstrap with 5,000 resamples to assess uncertainty in group means and pairwise differences; its confidence intervals were consistent with the original parametric analyses, but it did not increase the study’s effective sample size or statistical power.

The results are compatible with a self-reinforcing model of Alzheimer’s-associated neuronal tetraploidy. Oxidative stress could damage DNA, including genes involved in antioxidant responses and DNA repair; mutations in those genes could then impair genome maintenance and favor aberrant cell-cycle activity and genome duplication. Once tetraploidy was established, increased genomic stress could further elevate somatic mutation burden. Conversely, severe Alzheimer’s pathology could cause cellular stress and genome instability in already-tetraploid neurons, producing the same pattern. Because all three Alzheimer’s brains were at Braak stage V/VI and no early or mild cases were examined, the cross-sectional data cannot determine temporal order or causality. The clearest conclusion is therefore that Alzheimer’s-associated tetraploid neurons carry a specific enrichment of sSNVs with an oxidative-associated T>C pattern, particularly in oxidative-stress and DNA-repair genes, that merits validation in larger cohorts and with sequencing methods capable of confirming rare variants without amplification.

Subject of Research: Somatic single nucleotide variants in Alzheimer’s-associated tetraploid neurons

Article Title: Specific enrichment of somatic single nucleotide variants in Alzheimer-associated tetraploid neurons

Article References: López-Sánchez, N., Rábano, A., & Frade, J. M. (2026). Specific enrichment of somatic single nucleotide variants in Alzheimer-associated tetraploid neurons. Frontiers in Molecular Neuroscience, 19, Article 1929505. https://doi.org/10.3389/fnmol.2026.1929505

Image Credits: AI Generated

DOI: 10.3389/fnmol.2026.1929505

Keywords: Alzheimer’s disease, neuronal tetraploidy, somatic mutations, single nucleotide variants, whole-exome sequencing, oxidative stress, DNA repair, mutational signatures, post-mortem brain, genome instability, Specific, enrichment

The study’s bacterial tests detected a concentration-dependent mutagenic response in the Ames Salmonella reversion assay. The measured reversion response exceeded twice the spontaneous reversion frequency in the reported test conditions. Chloroform extracts generated a significantly stronger response with strain TA98 than with strain TA100, which the authors interpreted as evidence that frameshift mutagens were prevalent among the test samples.

DNA-repair-deficient Escherichia coli K-12 mutants also declined in survival after six hours of exposure. The recA and lexA mutants were more sensitive than their wild-type counterparts, providing further evidence of DNA-damaging potential. Because the assays tested mixed solvent extracts, they did not establish which individual contaminant produced each response or how the compounds interacted.

Plant assays showed effects on cell division, chromosomes and early growth. In Allium cepa, or onion, the mitotic index decreased from 51.63% to 20.62% across the tested concentration range, while the frequency of chromosomal abnormalities increased from 2.33% to 26.17%. The study’s highlights specifically reported chromosomal aberrations reaching 26.17% at 100% extract concentration.

In Vigna radiata, or mung bean, seeds exposed to the extracts showed reduced germination and seedling growth. Root-tip damage was also observed, and confocal microscopy detected reduced viability in root cells. These measurements indicate inhibition of plant growth and cellular injury under the assay conditions, but they do not by themselves identify the mechanism responsible for every observed effect.

Computational analysis complemented the laboratory results by examining possible molecular interactions. Docking calculations followed by 100-nanosecond molecular-dynamics simulations indicated stable binding between selected contaminants and molecular targets involved in nucleotide biosynthesis, DNA replication, topological regulation and cell division. The models therefore identified plausible routes through which the bioactive compounds might interfere with DNA-related processes and mitosis.

Stable interactions in a simulation remain predictions that require biological confirmation: the analysis did not demonstrate that the compounds reached the corresponding targets in living organisms or that any single interaction caused the effects seen in the bacterial and plant assays. Taken together, the results provide convergent evidence that the tested Ganges River water extracts contain chemically diverse emerging contaminants with mutagenic, genotoxic and phytotoxic activity in the selected laboratory systems. The research scope is limited to chemical identification, controlled bioassays and computational modelling of sampled water extracts.

It did not directly measure human exposure, clinical effects or the distribution of contaminants throughout the river, and its findings should not be interpreted as evidence that drinking untreated river water causes illness.

Subject of Research: Laboratory assessment of mutagenic, genotoxic and phytotoxic effects of emerging contaminants in Ganges River water extracts.

Article Title: Cyto-genotoxic potential and in silico analysis of emerging contaminants of the Ganges River water

Article References: Akhtar, S., & Malik, A. (2026). Cyto-genotoxic potential and in silico analysis of emerging contaminants of the Ganges River water. Environmental Monitoring and Assessment, 198(11), Article 1235. https://doi.org/10.1007/s10661-026-16073-8

Image Credits: AI Generated

DOI: 10.1007/s10661-026-16073-8

Keywords: Ganges River, emerging contaminants, mutagenicity, genotoxicity, Ames assay, DNA repair, chromosomal abnormalities, plant growth inhibition, molecular docking, molecular dynamics, Cyto-genotoxic, potential

The concept has been examined in ecological, medical and agricultural settings, including adaptation to environmental conditions, disease resistance and tolerance of physical and chemical stressors. The authors argue that the mechanisms contributing to this resistance are interdependent and may involve changes in genes, proteins, enzymes, metabolic pathways and biological networks. Oxidative stress and other damaging agents can produce several forms of DNA injury, including single-strand breaks, double-strand breaks, base and nucleotide modifications, cross-links and dimers.

The resulting damage depends on the damaging agent and on factors such as species, tissue, age, experimental design, cell-cycle phase and physiological state. Cells respond through the DNA damage response, which detects injuries and coordinates repair or apoptosis; related antioxidant and chaperone defence systems may also be activated. Particular attention is given to double-strand breaks, which the review describes as potentially lethal and which can be repaired through homologous recombination or non-homologous end joining.

It also discusses direct reversal of DNA damage, base excision repair, mismatch repair and nucleotide excision repair. Quantifying radiation-induced double-strand breaks can help evaluate and predict cellular or organismal responses to ionising radiation in occupational, accidental and medical settings. Results summarized from the authors’ experiments with the green alga Chlamydomonas reinhardtii, the yeast Saccharomyces cerevisiae and the extremophile Chlorella vulgaris showed differences among strains in DNA susceptibility and double-strand-break repair capacity.

The radio-resistant Chlamydomonas hybrid H-3 had several-fold higher potential for rejoining double-strand breaks than the comparison strains. The authors present these differences as possible contributors to genotype resistance rather than proof that repair capacity alone causes resistance. Mutant experiments with Chlamydomonas strains UVS-10, characterized as deficient in rec-repair, and UVS-14, deficient in mismatch repair, supported the involvement of these repair pathways in genotype resistance to different DNA-damaging factors.

The review also notes that published findings about the contributions of DNA susceptibility and repair capacity have been contradictory, leaving their relative roles incompletely resolved. Heat shock proteins include small HSPs with molecular masses of 10–30 kDa and the HSP40, HSP60, HSP70, HSP90 and HSP100 families. Small HSPs help prevent irreversible aggregation and allow aggregated proteins to be accessed by HSP70 and ClpB/HSP104 chaperones.

HSP70 participates in protein folding, transport, complex assembly, refolding and degradation, while HSP90 acts with other chaperones in later protein-maturation steps. These functions contribute to proteostasis and cellular survival during stress. The review identifies HSP27, HSP70, HSP90 and HSP110 as chaperones associated with regulation of double-strand-break repair, while HSP90 is reported to be required for both homologous recombination and non-homologous end joining.

HSPs are rapidly induced after DNA-damaging exposure and have been identified at DNA-repair sites by confocal microscopy. In mammalian cells, HSP110 has been associated with DNA-repair signalling, and blocking chaperones has increased tumour-cell sensitivity to drugs in the cited studies. These observations do not establish that chaperones directly repair damaged DNA.

Plant heat shock transcription factors regulate HSP expression and downstream antioxidant-enzyme genes. Reactive oxygen species can act as signals in this network, through which HSPs, superoxide dismutase, catalase, peroxidases and glutathione S-transferases contribute to stress tolerance. Overexpression of small HSP17.8 in Arabidopsis and HSP16.9 in tobacco has been associated with increased antioxidant-enzyme activities.

In the Antarctic Chlorella vulgaris strain, high constitutive levels and marked overproduction of HSP70B after heat stress correlated with increased resistance to UV-B irradiation and more clearly expressed photoreactivation and dark repair. The authors propose that HSP70B overproduction together with effective DNA repair may help explain survival in extreme Antarctic conditions and may serve as an indicator of oxidative stress. Overall, the review identifies accelerated DNA repair and activation of the DNA damage response as important components of genotype resistance, including tumour resistance to radio-chemotherapy.

It proposes that chaperones contribute indirectly through their interactions with repair proteins and their broader role in stress survival. The reviewed evidence remains mixed on the relative importance of DNA susceptibility and repair capacity, and the discussion does not demonstrate clinical efficacy for blocking individual chaperones or establish their agricultural applications directly.

Subject of Research: Relationships among chaperone overproduction, oxidative-stress resistance and DNA-repair regulation

Article Title: Does overproduction of chaperone proteins favour the repair of DNA injuries induced by oxidative stress? (Mini review)

Article References: Chankova, S. G., Yurina, N. P., Todorova, T. I., & Parvanova, P. N. (2023). Does overproduction of chaperone proteins favour the repair of DNA injuries induced by oxidative stress? (Mini review). BioRisk, 20, 7-22. https://doi.org/10.3897/biorisk.20.97569

Image Credits: AI Generated

DOI: 10.3897/biorisk.20.97569

Keywords: oxidative stress, heat shock proteins, DNA repair, genotype resistance, double-strand breaks, cellular stress, plant stress tolerance, protein homeostasis, mini-review, Does, overproduction, chaperone

The analysis assessed two error-prone pathways that generally serve as backup mechanisms when DNA double-strand breaks cannot be repaired through homologous recombination. Deletion patterns are described as “putative” scars, meaning that the genomic analysis was used to infer association with these repair processes rather than directly measuring pathway activity. The study’s purpose was to determine how extensively such patterns occur across tumor types and whether they are linked solely to homologous-recombination deficiency.

Although Alt-EJ-associated deletion burdens were generally higher in homologous-recombination-deficient tumors, the pattern varied by cancer type. Prostate adenocarcinoma and hepatocellular carcinoma had elevated numbers of SSA-associated deletions despite low homologous-recombination-deficiency scores. The researchers also found that SSA-associated deletions were more frequent in SINE-rich genomic regions. Among homologous-recombination-proficient lymphoid lineage tumors, these deletions showed pronounced enrichment near transcription start sites. Together, the reported results suggest that the genomic context of the deletion was associated with different dimensions of DNA-break repair activity beyond homologous-recombination deficiency alone.

The findings are based on the supplied abstract of an open-access BMC Cancer research article; the full study methods and results were not available for independent assessment. The deletions are therefore presented as putative pathway-associated signatures, and the abstract does not establish that the patterns directly quantify repair-pathway engagement. The publisher also states that the accessible article is an early version of peer-reviewed, accepted research, carries a permanent DOI, and may undergo further editorial revision before the final version of record.

Subject of Research: Genome-wide analysis of deletion patterns associated with SSA and alternative end joining across 17 cancer types

Article Title: Pan-cancer genomic scars of alternative end joining and single-strand annealing

Article References: Modi, A., Zito, A., & Parmigiani, G. (2026). Pan-cancer genomic scars of alternative end joining and single-strand annealing. BMC Cancer. https://doi.org/10.1186/s12885-026-16895-2

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16895-2

Keywords: cancer genomics, DNA repair, homologous recombination, single-strand annealing, alternative end joining, genome instability, tumor deletions, pan-cancer analysis, Pan-cancer, genomic, scars, alternative

Glioblastoma is an aggressive primary malignant brain tumor characterized by diffuse invasion, rapid progression and resistance to conventional therapy. Although maximal safe resection followed by radiotherapy and temozolomide remains standard care for newly diagnosed disease, durable control is difficult and recurrence is almost inevitable. A major reason is the tumor’s metabolic plasticity. Many glioblastoma cells favor aerobic glycolysis, converting glucose-derived pyruvate into lactate even when oxygen is available, while poorly organized blood vessels create hypoxic regions that further stimulate glycolysis. This combination produces pronounced lactate accumulation and regional metabolic heterogeneity. Lactate can move among tumor regions and cell populations through monocarboxylate transporters, particularly MCT1 and MCT4, allowing metabolic cooperation between hypoxic, lactate-producing cells and better-oxygenated cells that may take it up as fuel.

Lactate’s effects are not confined to energy metabolism and extracellular acidification. Protein lactylation is the covalent addition of a lactyl group to lysine residues. In the canonical pathway, lactyl-CoA serves as the activated donor for this reaction, connecting cellular metabolism to chromatin regulation and protein function. Histone lactylation can alter transcriptional programs, whereas modification of non-histone proteins can influence protein stability, enzyme activity, DNA binding and signal transduction. The enzymes involved remain incompletely resolved. GTPSCS and ACSS2 have been implicated in generating lactyl-CoA, and p300 and KAT2A have been implicated as writers. A distinct, ATP-dependent route involving AARS1 and AARS2 can modify proteins without lactyl-CoA as an intermediate, although direct evidence for that route in glioblastoma is lacking. Sirtuins and histone deacetylases can remove lactyl groups, indicating that lactylation is reversible rather than permanent.

Glioblastoma does not simply generate more lactylation when glycolysis intensifies. Lactate abundance depends on the balance among production, uptake, export and use, while modification also depends on activated-donor availability, writer and eraser activity, and whether a particular lysine is accessible in the relevant protein. Accordingly, the review classifies the literature into tiers of mechanistic confidence. The strongest evidence involves a defined non-histone lactylation site validated through mass spectrometry, site-specific assays, competitive peptides, mutation or rescue. Histone mechanisms receive an intermediate classification when a specific site, enrichment at a regulatory region and functional perturbation are demonstrated. Effects linked only to lactate exposure, metabolic inhibition or global histone lactylation are considered suggestive. This distinction is important because reducing lactate can also change energy production, redox balance, acidity and signaling independent of lactylation.

Several histone pathways connect lactylation to glioblastoma growth. In preclinical glioma systems, hypoxia-associated HIF-1α signaling and H3K18 lactylation have been linked to increased YTHDF2 expression, BNIP3-dependent mitophagy and transcriptional programs that favor proliferation and hypoxic adaptation. Nuclear GTPSCS has been reported to generate lactyl-CoA and cooperate with p300, increasing H3K18 lactylation at the GDF15 promoter in models that also showed tumor growth and radioresistance. Separately, SUCLG2 knockdown reduced lactate and H4K16 lactylation, with the remaining H4K16 signal enriched at regulatory regions associated with proliferation and apoptosis. Another study linked H4K8 lactylation at the NUPR1 promoter to autophagosome–lysosome fusion and protective autophagy in glioblastoma cells, patient-derived material and in vivo models. These observations provide mechanistic support, but mutation of each histone residue was not used to prove causality in all cases.

Lactylation may also sustain glioma stem cells, the self-renewing malignant populations associated with recurrence. H3K18 lactylation has been reported to increase USP4 transcription, which stabilizes ANXA2 through deubiquitination and supports stem-cell phenotypes. Another study found that histone lactylation increased LINC01127 transcription, allowing this long noncoding RNA to regulate MAP4K4 in cis and activate JNK signaling associated with self-renewal. Non-histone modification can reinforce this metabolic state: lactylation of PTBP1 at lysine 436 stabilizes PFKFB4 messenger RNA, increases glycolytic flux and lactate production, and creates a positive-feedback loop between lactate accumulation and stem-cell maintenance. Site-specific non-histone evidence is particularly important here because the number of validated lactylated substrates in glioblastoma remains limited.

Treatment resistance is one of the clearest areas of convergence. Lactate-induced H3K9 lactylation at the MLH1 locus promotes an RNA-splicing event that reduces mismatch repair and is associated with temozolomide resistance. Reduced SIRT6 activity has also been linked to increased H3K9 lactylation at the MGMT promoter, greater MGMT expression and diminished temozolomide sensitivity. These associations involve both histone and non-histone substrates. In ALDH1A3-high glioma stem cells, lactylation of XRCC1 at lysine 247 increases its binding to importin-alpha and nuclear translocation, supporting single-strand-break repair after radiotherapy or temozolomide exposure. HAT1-catalyzed lactylation of RPA1 at lysine 88 enhances its binding to single-stranded DNA and homologous recombination, while a competitive peptide increased radiosensitivity in preclinical models. A separate pathway involving KU70 lactylation at lysine 317 enhances non-homologous end joining, reduces cytosolic DNA and limits cGAS–STING signaling. Blocking lactate transfer from tumor-associated macrophages to glioma stem cells or targeting KU70 lactylation improved responses to immune checkpoint blockade in immunocompetent intracranial models.

The microenvironment extends these effects beyond tumor cells. Lactate taken up by macrophages through MCT1 has been associated with H3K18 lactylation at the TNFSF9 promoter, M2-like polarization and glioma progression. Enhanced glucose metabolism has also been linked to immunosuppressive histone-lactylation programs in monocyte-derived macrophages. In glioma stem-cell and myeloid co-culture models, CBX3 was reported to bias p300 toward lactyl-CoA-dependent histone lactylation, increasing transcription of CD47 and limiting phagocytosis by microglia and macrophages. Another route links lactate to H3K18 lactylation at the ARNTL promoter and BMAL1 lactylation at lysine 123, increasing VEGFA expression and reducing bevacizumab sensitivity in cell, xenograft, animal and clinical-cohort analyses. These results implicate lactate exchange and lactylation in immune suppression, but lactate can also influence immune cells through acidity, receptor signaling and metabolic substrates independently of protein modification.

Therapeutic experiments have therefore targeted several points along the pathway. In glioblastoma models, inhibiting lactate dehydrogenase with stiripentol reduced lactate production and tumor growth, while MCT1 inhibition decreased glioma stem-cell viability and proliferation. Neither is specific to lactylation. Other preclinical strategies reduce lactate or alter its regulatory machinery, including PPARα activation, SIRT6 activation, GTPSCS knockdown and inhibition of a TREM1-dependent pathway. One site-directed approach used a competitive peptide against RPA1 lysine 88 lactylation and increased radiosensitivity in preclinical models. Separately, oxamate, an upstream intervention that reduces lactate production, enhanced CAR-T-cell activity in glioma xenografts while reducing H3K18 lactylation and immune-suppressive metabolic programs. These findings suggest possible combinations with radiotherapy, chemotherapy, anti-angiogenic therapy or immunotherapy, but they do not establish clinical efficacy. Major barriers include delivery across the blood–brain and blood–tumor barriers, possible effects on normal brain metabolism, incomplete understanding of lactylation writers, readers and erasers, and a lack of standardized site-specific measurements.

Translation also requires better biological and methodological resolution. Glioblastoma contains plastic malignant-cell states and distinct metabolic niches, so lactylation probably varies with oxygen availability, cell state and neighboring cell types. Spatial transcriptomics generally reveals expression associated with lactate metabolism rather than protein lactylation itself; direct spatial mapping will require modification-specific antibodies, spatial proteomics or site-resolved mass spectrometry. Existing patient-stratification models largely analyze lactylation-related gene expression in public transcriptomic datasets and have not demonstrated that they predict treatment response in actual clinical cohorts. Normal brain physiology also includes lactate metabolism and lactylation, raising safety questions if lactate production or the modification is broadly inhibited. The review’s central conclusion is therefore one of promise and restraint: lactylation is a credible mechanism connecting glioblastoma metabolism with progression and resistance, but clinically useful targeting will require site-specific interventions, patient-derived and immunocompetent models, direct biomarker measurement, standardized assays and prospective validation in patients.

Subject of Research: Protein lactylation in glioblastoma metabolism, malignant progression and treatment resistance

Article Title: Lactylation in glioblastoma: mechanisms and therapeutic perspectives

Article References: Huang, L., Huang, B., Kuang, S., & Yan, Y. (2026). Lactylation in glioblastoma: mechanisms and therapeutic perspectives. Frontiers in Cell and Developmental Biology, 14, Article 1940871. https://doi.org/10.3389/fcell.2026.1940871

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1940871

Keywords: glioblastoma, lactylation, lactate metabolism, cancer metabolism, epigenetics, glioma stem cells, treatment resistance, tumor immunity, DNA repair, brain tumor, mechanisms, therapeutic

DNA repair requires proteins both to carry out repairs and to recognize molecular signals associated with when and where repair is needed. Dr. Jean-François Couture, a full professor in the University of Ottawa Faculty of Medicine’s Department of Biochemistry, Microbiology and Immunology and the study’s co-corresponding author, said the work shows how changes that interfere with this recognition can compromise repair, threaten genome stability and ultimately contribute to disease. TONSL, a protein involved in maintaining genome integrity, emerged from the study as a central coordinator in this process.

The researchers found that TONSL interacts with H3.1 through several molecular binding pockets rather than through a single point of contact. Two pockets recognized specific modifications on the histone: methylation at one position and acetylation at another. These chemical marks are associated with DNA regions involved in regulating genes. Their results therefore indicate that DNA-repair recognition depends partly on the modification state of surrounding chromatin, including histone variants that can carry distinct molecular features recognized by other proteins. The binding pockets collectively allowed TONSL to interpret multiple signals associated with H3.1.

Human-cell experiments provided a disease-related test of this recognition mechanism. Mutations in a region of TONSL associated with sponastrime dysplasia weakened the protein’s ability to recognize H3.1, and the altered proteins failed to restore normal DNA repair function. Couture described this as evidence that the mutations disrupt the ability to coordinate repair machinery as cells prepare for division, allowing DNA damage to accumulate. The findings support a possible contribution of defective TONSL recognition to sponastrime dysplasia; they do not establish that the entire spectrum of the inherited skeletal disorder can be explained by this molecular defect.

The study builds on the team’s earlier work published in Science in 2022. Since then, new collaborations enabled the researchers to extend their analysis from isolated proteins to interactions involving living human and mammalian cells, providing a broader view of how TONSL and H3.1 behave in cellular systems. Dr. Hossein Davarinejad, the first author and a postdoctoral fellow in Couture’s laboratory, said the team next plans to investigate other proteins involved in DNA repair pathways and conduct structural studies of larger parts of the repair machinery. Overall, the experiments show that protecting genetic information involves more than executing repair: the repair system must also interpret the chemical features of chromatin to coordinate the response appropriately.

Subject of Research: Molecular recognition of histone H3.1 modifications by TONSL in DNA repair and genome stability

Article Title: Unravelling DNA repair: uOttawa-led team shows how cells protect their genetic blueprint

Article References: Unravelling DNA repair: uOttawa-led team shows how cells protect their genetic blueprint. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: TONSL, DNA repair, histone H3.1, genome stability, chromatin, protein recognition, sponastrime dysplasia, cell division, University of Ottawa, Unravelling, repair, uOttawa-led

Most plant cytidine base editors are built as one continuous protein. A catalytically weakened version of Cas9, known as SpCas9 nickase, is fused to a cytidine deaminase enzyme. This arrangement keeps the enzyme close to the single-stranded DNA exposed when the guide RNA directs the nickase to its target. The strategy is generally powerful, but prolonged contact can allow the deaminase to modify several nearby bases, create unwanted DNA-repair outcomes or contribute to small insertions and deletions, or indels. Testing a new deaminase, linker or Cas9 variant can also require rebuilding and reconstituting the entire fusion protein, a laborious process in plants because transformation is slow.

Free-BE takes a deliberately simple approach to this design problem. The nickase and CDA1 are encoded on separate plasmids and expressed independently, without an intein, engineered protein interaction or RNA-based recruitment system. The central hypothesis was that the two proteins could still work together if they encountered the same target temporarily. If the deaminase were not tethered continuously to the nickase, it might spend less time exposed to the target DNA. That shorter exposure could preserve useful C-to-T conversions while reducing collateral editing. Researchers compared this modular configuration, called Fused-BE, with a conventional nCas9–CDA1 fusion in the moss APT reporter system, where mutations that inactivate the APT gene confer resistance to the toxic adenine analogue 2-fluoroadenine.

In moss, both systems edited APT, but the fused version was clearly more productive. With one guide RNA, Fused-BE inactivated APT in 7.1% of regenerating plants, compared with 2.9% for Free-BE; with the second guide, the rates were 5.6% and 1.9%, respectively. Expression of the nickase alone produced negligible mutation frequencies of 0.004% and 0.008%, showing that most of the activity attributed to Free-BE came from its deaminase component. The lower yield was therefore a real limitation, but it did not indicate that independent expression prevents the enzyme from functioning at a guide-defined site.

The quality of the resulting edits differed as strikingly as their frequency. With the first guide, 52.8% of the mutations produced by Fused-BE contained indels, versus 7.1% with Free-BE—a roughly sevenfold reduction that was not merely a consequence of the system’s lower overall efficiency. Free-BE also produced a higher proportion of plants carrying only one edited cytidine: 55% with the first guide and 82% with the second, compared with 6% and 49% for the fused editor. The two architectures did not generate identical molecular outcomes, however. Free-BE produced fewer canonical C-to-T transitions and relatively more transversions, especially C-to-G, suggesting that changes in the timing and proximity of the deaminase may influence how the resulting U:G mismatch is repaired.

Targeted safety checks did not reveal unintended mutations in the candidate off-target sites examined in moss. The researchers identified four potential off-target loci for one guide using a sequence-similarity score and sequenced them in plants edited with either system. No mutations were detected at these sites in the tested lines. That finding is encouraging but limited: the analysis covered only a few predicted genomic locations for a single guide and did not measure genome-wide off-target activity, RNA editing or off-target effects in maize and wheat. The result therefore supports the need for broader specificity studies rather than establishing genome-wide specificity for Free-BE.

Free-BE then moved into a crop-based reporter test in maize. Researchers engineered a nonfunctional blue fluorescent protein so that one C-to-T edit would restore a functional green fluorescent protein. Maize protoplasts receiving the fused editor converted 1.5% of reporter molecules, while those receiving Free-BE achieved 0.6% conversion. Negative controls produced almost no GFP-positive cells. The experiment demonstrated that unlinked components can generate targeted base editing in maize cells, but because the assay measured correction of a transient reporter rather than editing of an endogenous maize gene, stable maize experiments are still needed to establish how the system performs in the crop genome.

Wheat provided the most demanding validation, involving Agrobacterium-mediated transformation of the Fielder cultivar and two guide RNAs directed at TaGASR7 and TaLOX2. Each guide perfectly matched three homoeologous copies, giving six possible endogenous targets for multiplex editing. Of 291 transformed T0 plantlets carrying Fused-BE, 235 contained an edited cytidine at one or more targets, an editing rate of 80.8%. Free-BE edited at least one target in 33 of 77 transformants, or 42.9%. Both systems could multiplex several loci: 9.1% of edited Free-BE plants carried changes in five of the six target genes, while 11.5% of edited Fused-BE plants showed changes in all six. The conventional editor therefore remained more efficient, but the modular system retained considerable activity and generated combinations of edits across multiple wheat homoeologs.

The wheat sequence data also reproduced Free-BE’s cleaner editing profile. At the TaLOX2 target, which contains seven cytidines in the guide’s spacer, 50% of Free-BE-edited plants carried one edited cytidine, compared with 21.7% for Fused-BE. Dual and triple edits were correspondingly less frequent with Free-BE, occurring in 10.0% and 3.8% of plants rather than 22.6% and 12.6%. Fused-BE also generated occasional edits near the guide’s PAM-proximal edge and outside the spacer region, whereas Free-BE did not show those events in the analyzed wheat plants. Unlike in moss, Free-BE did not consistently increase C-to-G or C-to-A transversions in wheat, indicating that the effect of separating the editor components may depend on the plant species, target sequence and biological context.

Overall, the study presents Free-BE as a precision-first alternative to the speed and efficiency of fused base editing. Its principal advantages are fewer indels, a greater likelihood of isolated single-cytosine changes, no detected edits beyond the predicted window in the wheat dataset, and a modular design that allows deaminases, Cas9 variants and expression strategies to be tested without repeatedly constructing a complete fusion. Its disadvantages are equally clear: editing frequencies were consistently lower, and the spectrum of nucleotide substitutions could be less predictable in moss. Optimizing the expression levels and timing of the two components may improve performance, while stable maize tests and comprehensive DNA and RNA off-target analyses will be needed to define the system’s full utility. For precision breeding, the results point to a promising bargain: a lower chance of producing the desired allele may be acceptable if it comes with a lower chance of altering the genetic neighborhood around it.

Subject of Research: Evaluation of a modular cytidine base-editing strategy in moss, maize, and wheat

Article Title: Validation of a Modular Base Editing Strategy, Free‐BE, in Physcomitrium patens, Maize, and Wheat

Article References: Guyon‐Debast, A., Javelle, M., Perroud, P.-F., Pichon, J.-P., Paul, W., & Nogué, F. (2026). Validation of a Modular Base Editing Strategy, Free‐BE, in Physcomitrium patens , Maize, and Wheat. Plant Direct, 10(10), Article e70196. https://doi.org/10.1002/pld3.70196

Image Credits: AI Generated

DOI: 10.1002/pld3.70196

Keywords: base editing, CRISPR, genome editing, cytidine deaminase, wheat, maize, moss, plant breeding, DNA repair, precision breeding, Validation, Modular

The gene at the center of the study is ogt, which encodes O6-methylguanine DNA methyltransferase, or Ogt. This enzyme belongs to a family of suicide repair proteins that directly reverse a particularly dangerous form of DNA damage: the alkylation of guanine at its O6 position. If left unrepaired, O6-methylguanine mispairs with thymine during replication, producing mutations that can cripple the bacterium or, in some contexts, help it evolve resistance to stresses. Earlier work by other groups has shown that alkyltransferase systems contribute to the virulence of Salmonella enterica, making the question of how ogt is switched on and off a matter of genuine pathogenic relevance. Until now, however, the transcriptional regulation of ogt in Salmonella Typhimurium remained poorly characterized.

The regulatory suspect in this study was NarL, a response regulator from the two-component signaling systems that bacteria use to sense and adapt to environmental change. NarL is activated as part of the nitrate and nitrite respiration pathway, which becomes important when Salmonella finds itself in the oxygen-poor depths of the intestinal tract. Previous research from the same and other laboratories had implicated narL in the pathogenesis of Salmonella Typhimurium under anaerobic conditions, and deletion of both fnr and narL, the two major anaerobic regulators, has been shown to compromise the bacterium’s ability to colonize a mouse model. The idea that such a metabolism-oriented regulator might also reach into the DNA repair program was intriguing enough to test directly.

To do so, the team first needed purified NarL protein. They cloned the narl gene into the pET32a expression vector and produced the recombinant protein in Escherichia coli BL21 (DE3), a standard workhorse strain for protein expression. On the DNA side, they selected the promoter region of the ogt gene, amplified it, and cloned it so that both its binding behavior and its activity could be evaluated. This combination of a purified regulator and a defined promoter fragment set the stage for a series of experiments designed to answer a deceptively simple question: does NarL physically attach itself to the ogt promoter, and if so, does that attachment matter for gene expression?

The first line of evidence came from electrophoretic mobility shift assays, a classic technique in which a DNA fragment is mixed with a candidate binding protein and run through a gel. If the protein binds, the DNA-protein complex migrates more slowly than the free DNA, producing a visible shifted band. The assays showed that NarL interacts specifically with the ogt promoter, indicating a direct physical association rather than an indirect effect mediated by other cellular components. Molecular docking simulations were used to complement this picture, providing a structural view of how the regulator might engage the promoter DNA.

The biophysical confirmation came from isothermal titration calorimetry, a technique that measures the heat released or absorbed as one molecule binds to another and thereby yields thermodynamic parameters for the interaction. The ITC measurements supported a favorable binding interaction between NarL and the ogt promoter, with a calculated free energy change of −9.42 kilocalories per mole. A negative free energy of that magnitude indicates a spontaneous, thermodynamically stable interaction, consistent with a regulator that genuinely recognizes its target sequence rather than sticking to DNA nonspecifically. Together, the EMSA, docking, and ITC results formed a converging case that NarL is a bona fide DNA-binding partner of the ogt promoter.

Physical binding alone does not prove biological relevance, so the researchers turned to living bacteria. Using quantitative reverse-transcription PCR, they compared ogt transcript levels between wild-type Salmonella Typhimurium and a strain in which narl had been deleted. The deletion significantly reduced ogt expression, with the difference reaching statistical significance at P ≤ 0.01. A β-galactosidase reporter assay, in which the ogt promoter drives expression of the lacZ gene so that promoter activity can be measured through an enzymatic readout, told the same story: removing narl significantly decreased promoter activity relative to the wild-type strain.

Perhaps the most convincing experiment was the rescue. When the researchers supplemented the narl deletion strain with exogenous recombinant NarL protein, ogt expression was restored. That reversal is important because it argues that the loss of ogt expression was specifically due to the absence of NarL rather than to some collateral damage caused by deleting the gene. It also demonstrates that the regulatory relationship operates at the level of the protein finding its target, a direct and mechanistically interpretable connection between regulator and promoter.

The broader significance of the study lies in what it says about how Salmonella integrates its survival strategies. NarL sits at the junction of nitrogen metabolism, responding to nitrate and nitrite availability during anaerobic respiration. Ogt sits at the junction of genome maintenance, reversing alkylation damage that can arise from reactive nitrogen and oxygen species generated during infection. By connecting the two, the study suggests a model in which the bacterium ramps up DNA repair capacity in response to environmental signals associated with nitrosative stress, the chemically hostile conditions it encounters in inflamed host tissues. The authors propose that this NarL-ogt link may contribute to bacterial survival under exactly those conditions.

There are caveats worth keeping in mind. The study reports no animal experiments, and the authors note that no datasets were generated or analyzed beyond those described in the work itself, so the physiological consequences of the NarL-ogt connection in a living host remain to be tested. The precise binding sequence within the promoter, the exact structural contacts revealed by docking, and the interplay with other regulators of ogt expression are all questions for future work. Nevertheless, the convergence of in vitro binding data, thermodynamic measurements, structural modeling, and in vivo expression analysis makes a strong case that NarL is a genuine transcriptional regulator of the ogt DNA repair gene. For a pathogen whose success depends on both metabolic flexibility and genomic integrity, that connection may prove to be more than a molecular curiosity.

Subject of Research: Binding of the NarL response regulator to the ogt gene promoter in Salmonella Typhimurium

Article Title: Binding analysis of the response regulator NarL protein to the promoter of the O6-methylguanine-DNA methyltransferase (ogt) gene in Salmonella Typhimurium

Article References: Sahoo, P. R., Kumar, A., Pashupathi, M., & Sahoo, J. R. (2026). Binding analysis of the response regulator NarL protein to the promoter of the O6-methylguanine-DNA methyltransferase (ogt) gene in Salmonella Typhimurium. Molecular Biology Reports, 53(1), Article 1535. https://doi.org/10.1007/s11033-026-12687-w

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12687-w

Keywords: Salmonella Typhimurium, NarL, ogt, DNA repair, gene regulation, EMSA, isothermal titration calorimetry, molecular docking, RT-qPCR, promoter activity, nitrosative stress, response regulator