Interstrand crosslinks, or ICLs, are among the most cytotoxic forms of DNA damage because they covalently tether the two strands of the double helix to one another, blocking both DNA replication and transcription. Cisplatin, a platinum-based drug, induces these crosslinks as part of its antitumor arsenal, and the resulting suppression of transcription contributes significantly to the drug’s ability to kill rapidly dividing cancer cells. However, cells possess a dedicated pathway known as transcription-coupled repair that can remove such lesions from actively transcribed genes, and this repair capacity can mitigate cisplatin’s effects, contributing to treatment resistance in some tumors. Understanding exactly how the crosslink stalls the polymerase, and how that stall is recognized by the repair machinery, is therefore of direct clinical relevance.

The Zhejiang team assembled defined RNA polymerase II elongation complexes on DNA templates containing a site-specific cisplatin-induced interstrand crosslink, positioning the lesion at various distances from the enzyme’s active site. By vitrifying these complexes and imaging them with cryo-electron microscopy, the researchers were able to reconstruct a molecular movie of sorts, following the polymerase as it advanced toward the crosslink and ultimately ground to a halt. The eight captured states span the journey from the initial approach of the lesion through the final stalled configuration, offering a step-by-step structural narrative that has never before been available for this class of DNA damage.

The most striking discovery emerged when the polymerase reached the crosslink itself. Rather than simply blocking progress like a physical roadblock, the crosslinked guanine bases underwent an unexpected conformational transformation. The enzyme actively remodeled the crosslink, prying the damaged guanines into a novel configuration positioned above the bridge helix, a structural element of the polymerase that plays a central role in translocating DNA and RNA through the enzyme. This rearrangement had not been observed for any other type of transcription-blocking lesion and reveals RNA polymerase II in an unanticipated role: that of a structural remodeler of the very damage it encounters.

The consequence of this remodeling is functionally decisive. By relocating the crosslinked base above the bridge helix, the polymerase prevents the damaged guanine from entering the active site, the catalytic chamber where templated nucleotide addition normally occurs. With the lesion physically excluded from the position where it would need to reside to serve as a template, transcription cannot proceed in the conventional manner. The structural data show that the remodeled crosslink creates an empty nucleotide-binding site poised in an abnormal configuration, setting the stage for a secondary failure mode that the researchers characterized in detail.

That secondary failure is ATP misincorporation followed by backtracking. Because the active site is left in an aberrant state, the polymerase can misinsert adenosine triphosphate opposite the position where the crosslinked guanine should have been read. Following this misincorporation event, the enzyme undergoes backtracking, a process in which the polymerase slides backward along the DNA and RNA, extruding the freshly synthesized 3′ end of the RNA transcript from the active site. Backtracking is a well-known mechanism of transcriptional arrest, and the new structures demonstrate how the remodeled crosslink actively drives the enzyme into this arrested configuration rather than merely obstructing forward motion.

The study also examined oxaliplatin, another clinically important platinum chemotherapy drug, and found that its interstrand crosslinks stall polymerase II through a conserved mechanism. Notably, the structural analyses revealed that when the platinum crosslink sits several nucleotides downstream of the active site, the polymerase drives the platinum adduct from the minor groove of the DNA helix into the major groove, and the crosslinked guanine on the non-template strand migrates toward the upstream side of the complex as the lesion approaches the catalytic center. These observations, together with experiments using alternative DNA sequences, demonstrated that the remodeling behavior is not an artifact of a particular template but a general property of how polymerase II handles platinum crosslinks.

A central question in transcription-coupled repair concerns what happens after the polymerase stalls. Cockayne syndrome protein B, or CSB, is an ATP-dependent translocase that is recruited to stalled polymerase II and is considered the initiating factor of transcription-coupled repair. One might expect CSB to either help the polymerase bypass the lesion or actively displace the stalled enzyme to clear the way for repair enzymes. The new data show that CSB does neither. In the reconstituted system, CSB neither promoted bypass of the cisplatin crosslink nor displaced the stalled polymerase, and the transcription factor TFIIS, which can stimulate RNA cleavage and restart arrested polymerases, likewise failed to rescue transcription through the lesion. This failure to resolve the blockage effectively commits the crosslinked site to the transcription-coupled repair pathway, ensuring that the damage is flagged for processing rather than erroneously bypassed.

The structural comparisons revealed additional mechanistic elegance. The fork loop-2 region of the polymerase was observed to separate the template and non-template DNA strands at the downstream fork of the transcription bubble, and this separation appears to facilitate the migration of the crosslinked non-template guanine as the lesion is remodeled. Furthermore, alignment of the cisplatin-stalled complexes with previously determined structures of polymerase II bound to CSB homologs, including yeast Rad26 and the human CSB-CSA-UVSSA complex, showed that the crosslink-stalled enzyme adopts a conformation competent for recruiting these repair factors, mirroring the way polymerase II arrested by bulky lesions on the template strand presents itself to the repair machinery.

The implications of this work extend from basic molecular biology to the clinic. By identifying RNA polymerase II as an active remodeler of cisplatin-induced interstrand crosslinks and defining the structural basis of the resulting stall, the study fills a long-standing gap in our understanding of how platinum drugs exert their transcription-blocking effects at atomic resolution. Because the efficiency of transcription-coupled repair influences cellular sensitivity to cisplatin, with repair-deficient cells such as certain testis tumor cells showing heightened drug sensitivity, the molecular details uncovered here could inform strategies to modulate repair pathways and improve therapeutic outcomes. The cryo-electron microscopy maps and atomic models have been deposited in public databases, ensuring that the structural framework established by the Zhejiang team will serve as a foundation for future studies of crosslink repair, polymerase stalling, and the cellular response to platinum-based chemotherapy.

Subject of Research: Structural mechanism of transcription stalling by cisplatin-induced DNA interstrand crosslinks

Article Title: Transcription remodeling and stalling by cisplatin-induced interstrand crosslinks

Article References: Zhu, L., Zhao, W., Ye, L., Liu, Y., Deng, W., Qian, B., Yang, X., & Xu, J. (2026). Transcription remodeling and stalling by cisplatin-induced interstrand crosslinks. Nature Chemical Biology. https://doi.org/10.1038/s41589-026-02338-3

Image Credits: AI Generated

DOI: 10.1038/s41589-026-02338-3

Keywords: cisplatin, interstrand crosslink, RNA polymerase II, transcription-coupled repair, cryo-electron microscopy, DNA damage, Cockayne syndrome protein B, oxaliplatin, backtracking, platinum chemotherapy, bridge helix, DNA repair

The study is grounded in the Common-Sense Model of self-regulation, a well-established framework in health psychology that describes how people respond to illness in much the same way they respond to any other threat. According to the model, patients build internal, common-sense representations of their condition: What is it? How long will it last? Can I control it? How much will it disrupt my life? These illness perceptions then drive coping behavior, and coping in turn shapes emotional and physical outcomes. The Chinese research team set out to test whether this chain holds for CIPN, a condition that is often dismissed as a manageable side effect yet frequently imposes a heavy burden on daily functioning, sleep, mood, and quality of life.

To do so, the investigators conducted a two-center cross-sectional survey of 563 adults who were receiving platinum-based chemotherapy and reported CIPN symptoms. Platinum drugs such as oxaliplatin and cisplatin are mainstays of treatment for colorectal, ovarian, lung, and many other cancers, and they are notorious for damaging the peripheral nerves. Participants completed validated questionnaires measuring CIPN symptom severity, psychological distress, illness perceptions, positive coping strategies, mindfulness, and physical activity. The researchers then used structural equation modeling with bootstrapping, a statistical technique that estimates networks of direct and indirect relationships while accounting for measurement error, to test whether positive coping mediated the link between illness perceptions and outcomes, and whether mindfulness moderated those pathways. Covariates were adjusted throughout the analysis to reduce the risk of confounding.

The results were striking. Patients who perceived their neuropathy as more threatening, more chronic, less controllable, or more disruptive reported significantly greater CIPN symptom burden and higher levels of psychological distress. But the more important finding concerned what lay in between. Positive coping, meaning active, constructive strategies for managing the condition, partially mediated these associations. In other words, part of the reason threatening illness perceptions translated into worse outcomes was that they undermined patients’ ability to cope constructively. The mediation was substantial: positive coping accounted for 51 percent of the total association between illness perceptions and symptom burden, and 37 percent of the association with psychological distress. The remaining portion reflects direct effects, suggesting that beliefs about the illness also influence outcomes through channels beyond coping.

The study then added a second psychological layer. Mindfulness, the capacity to attend to present-moment experience with openness and without judgment, moderated key pathways in the model. This means the strength of the relationships linking illness perceptions to coping and to outcomes varied according to patients’ mindfulness levels. In practical terms, the same degree of perceived threat appears to carry different consequences depending on how mindfully a patient relates to their symptoms. Patients with higher mindfulness may be better buffered against the cascade that turns frightening beliefs into escalating symptom burden and emotional distress, while those with lower mindfulness may be more vulnerable across these pathways. The finding positions mindfulness not as a cure for nerve damage but as a psychological amplifier or damper on the self-regulatory process.

The technical architecture of the analysis deserves attention because it strengthens the credibility of these conclusions. Structural equation modeling allowed the researchers to test an entire system of hypothesized relationships simultaneously rather than examining correlations one at a time. Bootstrapping, which involves repeatedly resampling the data to estimate the stability of indirect effects, provided confidence in the mediation results, following methods pioneered by Preacher and Hayes that have become standard in this field. The team also took explicit steps to control for common method bias, a known pitfall in self-report research, and used dynamic fit index cutoffs to evaluate model fit. The study was approved by the Ethics Committee of Nanjing Medical University, and all participants provided written informed consent.

Why does this matter clinically? CIPN has long frustrated oncologists because there is no reliably effective drug treatment for it. Dose reduction and treatment interruption are the main tools for prevention, but once neuropathy develops, options are limited. Recent research has explored cryotherapy, compression, exercise programs, electrical dry needling, and neural mobilization, with mixed and often modest results. Systematic reviews of exercise interventions have found improvements in some symptoms, balance, and strength, but effects vary widely across the many exercise modalities tested. Against this backdrop, the new study points to a complementary target that has been largely overlooked in routine oncology care: the patient’s own mental model of the condition.

The self-regulatory perspective reframes CIPN as a problem that unfolds in a feedback loop between body and mind. A patient who believes the numbness signals permanent, uncontrollable damage may withdraw from activity, disengage from self-care, and ruminate on worst-case scenarios, which can amplify both the perceived severity of symptoms and emotional suffering. A patient who understands the condition as manageable, temporary, or at least partially controllable is more likely to adopt positive coping strategies, such as seeking information, adapting daily routines, staying physically active, and maintaining social connection. The study’s mediation figures suggest that this coping pathway is not a marginal effect; it carries roughly half of the total relationship between beliefs and physical symptom burden.

The authors emphasize that their findings have direct implications for survivorship care. Interventions targeting illness perceptions, coping skills, and mindfulness may help patients better manage CIPN symptoms and psychological distress, supporting more comprehensive and integrated symptom management. Concretely, this could mean brief psychoeducational conversations during chemotherapy visits that correct catastrophic misinterpretations of neuropathy symptoms, structured coping-skills training, or mindfulness-based programs adapted for patients undergoing cancer treatment. Mindfulness interventions have shown promise in other clinical populations for reducing anxiety and improving acceptance, and the moderation findings here provide a theoretical rationale for testing them specifically in patients at high risk of CIPN-related distress.

As with any cross-sectional study, there are limits to interpretation. The data capture a single moment in time, so the direction of the pathways, while theoretically grounded, cannot be definitively established; it is possible, for example, that heavier symptom burden also feeds back into more threatening illness perceptions. Self-report measures, however well validated, remain subject to individual differences in response style. Longitudinal and intervention studies will be needed to confirm that reshaping illness perceptions or raising mindfulness actually reduces symptom burden over the course of treatment. Even so, the study offers something oncology has lacked for CIPN: a coherent, testable psychological model of why some patients suffer more than others from the same nerve damage, and a set of modifiable targets, beliefs, coping, and mindfulness, that could be woven into supportive care. For the growing population of cancer survivors living with numb hands and painful feet, that shift in perspective may prove to be a meaningful part of the answer.

Subject of Research: Illness perceptions, coping, and mindfulness in chemotherapy-induced peripheral neuropathy symptom burden

Article Title: Illness perceptions and symptom burden in chemotherapy-induced peripheral neuropathy: a moderated mediation analysis from a self-regulatory perspective

Article References: Geng, Q., Gao, X., Zhao, Q., Ma, H., Xu, R., Luo, J., Tang, C., & Jin, Y. (2026). Illness perceptions and symptom burden in chemotherapy-induced peripheral neuropathy: a moderated mediation analysis from a self-regulatory perspective. Journal of Cancer Survivorship. https://doi.org/10.1007/s11764-026-02081-7

Image Credits: AI Generated

DOI: 10.1007/s11764-026-02081-7

Keywords: chemotherapy-induced peripheral neuropathy, illness perception, self-regulation, positive coping, mindfulness, symptom burden, psychological distress, cancer survivorship, platinum chemotherapy, structural equation modeling, Common-Sense Model, supportive care