The review, published on 26 August 2026 by Xinyan Zou, Botao Zhang, Binxian Gu, Yong Gong, Yanchao Bai and Likui Zhang, focuses on NurA as a central component of a compact DNA end-resection machine. In archaeal cells, NurA works together with the HerA helicase and the Mre11-Rad50 complex. Their combined task is to process the broken ends of DNA and generate single-stranded DNA tails with a free 3′ end. These tails are essential substrates for homologous recombination, a repair pathway that uses an intact DNA molecule as a template to restore missing genetic information.

The first challenge after a double-strand break is not simply joining the broken ends. For homologous recombination to begin, the cell must carefully reshape the damaged DNA. One strand is progressively removed from each broken end, exposing the complementary strand as single-stranded DNA. This directional process, known as end resection, creates a molecular platform on which recombination proteins can assemble. The resulting 3′ single-stranded tails are particularly important because they can search for and pair with a matching sequence in an undamaged chromosome. NurA appears to perform a major part of the enzymatic cutting required to produce these tails, while HerA helps unwind the DNA and Mre11-Rad50 contributes to the initial recognition and processing of the break.

Structurally, archaeal NurA forms a toroidal dimer, producing a ring-shaped molecular assembly with a central channel. This architecture is more than a visual feature. A ring-shaped nuclease can help confine DNA within a defined catalytic environment, positioning the nucleic acid for controlled cleavage as it passes through or interacts with the channel. The dimeric arrangement also creates an extended surface for DNA binding and may help coordinate the movement of DNA with the action of the associated HerA helicase. According to the review, NurA and HerA can form a continuous channel, suggesting that DNA may be transferred directly from the helicase into the nuclease without freely diffusing into the surrounding cell.

NurA possesses two related but distinct catalytic capabilities. It can act as a 5′-to-3′ exonuclease, removing nucleotides sequentially from a DNA end, and it can also function as an endonuclease, cutting within a DNA strand rather than only at its terminus. These activities provide the enzyme with flexibility during repair. Exonucleolytic digestion can enlarge a resected region from an existing DNA end, while endonucleolytic cleavage may help initiate processing at particular DNA structures or positions. The balance between the two activities is likely to depend on the DNA substrate, the arrangement of the protein complex and the presence of partner enzymes, although the review emphasizes that important mechanistic questions remain unresolved.

The chemical engine behind NurA’s activity is a divalent metal ion. In particular, manganese ions, or Mn²⁺, are described as essential for catalysis. Like many nucleases, NurA is thought to use metal ions to organize the DNA substrate, activate water molecules and stabilize the negatively charged reaction intermediates that form when phosphodiester bonds are broken. The requirement for Mn²⁺ highlights the importance of the enzyme’s catalytic environment: without the appropriate metal cofactor, the chemical steps needed to cleave DNA cannot proceed efficiently. The review also summarizes the identification of amino acids that contribute to DNA binding and strand cleavage, helping define how NurA recognizes its substrate and positions the scissile phosphate bond for hydrolysis.

The NurA–HerA partnership is particularly significant because it links two physically different operations: DNA unwinding and DNA degradation. HerA is a helicase that uses energy from nucleotide hydrolysis to separate the two strands of the DNA duplex. NurA, positioned alongside it, can then process the exposed strand. Their continuous channel offers a possible explanation for how archaeal cells coordinate these reactions while minimizing the risk of uncontrolled DNA degradation. Rather than allowing a nuclease and helicase to operate independently, the paired system could guide DNA through a protected molecular corridor in which unwinding and resection are synchronized. The Mre11-Rad50 complex adds another layer of coordination by participating in the detection and early processing of broken chromosome ends.

This compact repair system is also important from an evolutionary perspective. NurA homologs are found across archaeal lineages and in some bacteria, but no NurA counterpart is known in eukaryotes. At the same time, eukaryotic cells possess more elaborate DNA end-resection pathways that perform related functions through different protein assemblies. The presence of NurA in archaea, together with its partnership with HerA and Mre11-Rad50, raises questions about how ancient DNA repair strategies were reorganized during the transition from prokaryotic ancestors to the first eukaryotic cells. The review presents NurA as a potentially valuable molecular marker for tracing which parts of double-strand break repair machinery were retained, replaced or lost during evolution.

Particular attention is drawn to the Asgard superphylum, a group of archaea considered especially relevant to studies of eukaryotic origins. Genomic surveys have identified widespread, previously uncharacterized NurA homologs in Asgard archaea. These proteins could reveal whether the structural and catalytic features observed in other archaeal NurA enzymes were already present in lineages related to the ancestors of eukaryotes. However, the review makes clear that Asgard-derived NurA proteins have not yet been experimentally characterized. Their biochemical activities, metal requirements, oligomeric states and interactions with HerA or Mre11-Rad50 remain open questions. Sequence similarity alone cannot establish whether these proteins possess the same dual nuclease activities or assemble into comparable DNA-processing channels.

The authors therefore identify structural biology and biochemistry as priorities for the next stage of research. Determining the three-dimensional structures of Asgard NurA proteins, ideally in complexes with DNA, HerA and metal ions, could show whether their active sites and central channels resemble those of previously studied archaeal enzymes. Complementary experiments could measure their exonuclease and endonuclease activities, define their substrate preferences and test how mutations in DNA-binding or catalytic residues affect repair-related reactions. Reconstituting the NurA–HerA–Mre11-Rad50 system outside the cell would be especially informative because it could reveal how each component contributes to end resection and whether the proteins form a stable, coordinated machine. By connecting molecular structure with biochemical function and evolutionary distribution, NurA research may help explain how cells across the domains of life learned to repair broken chromosomes—and why some lineages ultimately replaced this ancient strategy with entirely different molecular solutions.

Subject of Research: Archaeal NurA nuclease and its role in DNA double-strand break repair

Article Title: Archaeal NurA nuclease: structure, catalytic mechanism, and functional cooperation in DNA double-strand break repair

Article References: Zou, X., Zhang, B., Gu, B. et al. “Archaeal NurA nuclease: structure, catalytic mechanism, and functional cooperation in DNA double-strand break repair.” Applied Microbiology and Biotechnology (2026). https://doi.org/10.1007/s00253-026-14009-3

Image Credits: AI Generated

DOI: https://doi.org/10.1007/s00253-026-14009-3

Keywords: NurA nuclease; Archaea; DNA double-strand break repair; HerA helicase; Mre11-Rad50; homologous recombination; DNA end resection; Mn²⁺-dependent nuclease; Asgard archaea; molecular evolution

DNA is continuously exposed to chemical damage. Thousands of reactions occur inside every cell each day, and some of them alter DNA bases, break chemical bonds or interfere with the normal pairing of the two strands. Cells possess several repair systems that patrol the genome and correct many of these lesions. But repair is not perfect. Some damaged sites are recognized quickly and repaired efficiently, while others remain undetected long enough to be copied during cell division. Once a damaged base is converted into a different sequence through replication or faulty repair, the change may become permanent. “The rate at which mutations accumulate is a balance between the rate of damage and the rate of repair,” explains Dr. Ariel Afek, whose laboratory led the study. That balance is not uniform across the genome, and the new work helps reveal why.

Most research on genome instability has focused on mutations that are easy to observe because they remain as lasting changes in DNA. Afek’s team instead examined the temporary lesions that precede those changes. This distinction is important because a damaged DNA base does not inevitably become a mutation. Its fate depends on whether repair enzymes locate it, bind to it and remove it before the cell copies the damaged strand. To investigate these early steps, the researchers created a molecular chip containing thousands of short DNA molecules. Each molecule carried the same type of artificial damage, but the surrounding DNA letters were varied. This design allowed the scientists to compare repair activity at many sequence contexts while keeping the central lesion constant.

The experiments showed that the repair enzymes did not treat every damaged site equally. Their ability to recognize and bind the lesion depended on the precise combination of bases around it. The influence extended as far as five DNA positions upstream or downstream from the damaged base, indicating that the enzymes read a much larger molecular environment than the lesion alone. Noga Levy, a doctoral student in Afek’s laboratory and the study’s lead researcher, compared this behavior to an editor evaluating a word in context rather than in isolation. A damaged base may be chemically identical in two locations, yet the surrounding sequence can determine whether a repair protein notices it efficiently or passes it by.

The sequence effect was not simply a matter of the letters themselves. The researchers found that preferred DNA sequences shared physical characteristics, including distinctive shapes in the double helix. DNA is often represented as a uniform spiral staircase, but its structure changes subtly from one sequence to another. Some combinations of bases bend more easily, widen or narrow the grooves on the helix, or alter the distribution of electrical charge along the molecule. One of the repair enzymes studied by the team favored damaged sites embedded in sequences that create an unusually narrow region of the double helix. Such structural variation can provide a recognition signal that complements the chemical features of the damaged base.

To understand the molecular basis of this preference, the Weizmann researchers collaborated with a group led by Prof. Brian P. Weiser at Rowan University in New Jersey. Using computer simulations, the scientists examined how the repair enzyme moved across DNA and interacted with the region surrounding the lesion. The simulations indicated that one amino acid in the enzyme scans the local DNA structure. It is attracted to the negative electrical charge associated with the narrow helical region, helping guide the protein toward sequences with the appropriate shape. This model illustrates how DNA repair can depend on both chemistry and mechanics: the enzyme is not only searching for a damaged base, but also sensing the architecture and electrostatic landscape of the surrounding double helix.

The team then asked whether these biochemical preferences could be detected in the human genome after millions of years of evolution. One common form of genomic damage occurs when a cytosine, or C base, is chemically altered and no longer pairs correctly with guanine. Several important repair enzymes identify and remove the incorrect base, restoring the proper sequence. The researchers reasoned that genomic regions where a particular repair enzyme operates efficiently should preserve more cytosines, because damage at those sites would be more likely to be corrected. In regions where repair is inefficient, comparable damage should more often escape correction and accumulate as mutations. Analysis of genomic data revealed a correlation consistent with this prediction for one of the enzymes. The result suggests that repair preferences are not merely laboratory curiosities; over evolutionary time, they can influence which sequences remain stable and which become progressively altered.

That observation has implications for interpreting human evolution. When scientists identify genetic changes that became common in modern humans, they often ask whether those changes were favored because they helped people adapt to environmental pressures. But not every widespread change necessarily reflects natural selection. Some may have accumulated because the DNA sequence was especially vulnerable to damage or because repair enzymes were less effective in that context. “To identify which genomic changes were adopted by humans to survive a changing environment, we must first understand which changes accumulate naturally due to the preferences of the repair mechanisms,” Afek says. Distinguishing selection from repair-driven mutation could make evolutionary analyses more precise, particularly in genomic regions with unusually high or low mutation rates.

The same principle may help explain the genetic history of cancer. A tumor typically begins when one cell accumulates mutations that alter growth control, DNA maintenance or communication with neighboring cells. As that cell divides, additional changes form characteristic combinations known as mutational signatures. These signatures can reveal the kinds of damage that occurred and the repair pathways that were active or defective. In the new study, the researchers found a relationship between the sequence preferences of the repair enzymes and mutation patterns observed in human tumors. One explanation is that damage to repair systems in cancer cells allows mutations to accumulate in genomic regions that were previously protected. Another is that evolution has tuned repair enzymes to recognize regions that are intrinsically more vulnerable. Although the study does not establish a single cause, it reinforces the idea that repair activity is a major force shaping cancer genomes.

The findings may ultimately have practical applications beyond understanding mutation. DNA repair enzymes are already used in biotechnology and gene-editing systems, where their ability to recognize particular structures can be harnessed to modify genetic material. Mapping the sequence and shape preferences of these proteins could allow researchers to design more precise molecular tools or engineer enzymes that protect vulnerable regions of the genome more effectively. Afek’s laboratory is extending the approach to additional repair mechanisms in work led by graduate student Noga Carmon. By studying repair as a process that combines damage recognition, sequence context, molecular shape and electrical charge, scientists may gain a more complete view of how cells preserve genetic information—and how failures in that preservation can drive disease.

Web References: Nature Communications article; DOI link

References: Nature Communications, DOI: 10.1038/s41467-026-74090-0

Keywords: DNA repair, mutations, genome stability, genetic damage, structural biology, DNA sequence context, cancer genomics, mutational signatures, evolution, gene editing