Topology Resetting During Transcription-Coupled Nucleotide Excision Repair

Transcription-coupled nucleotide excision repair (TC-NER) removes transcription-blocking lesions from active genes, but how lesion-stalled RNA polymerase II (RNAPII) is converted into a repair-accessible substrate remains incompletely understood. Active chromatin is dynamic but not topology-free. RNAPII elongation generates torsional stress that is buffered by nucleosome dynamics, chromatin remodelers, topoisomerases, and gene-body organization. Upon lesion-induced RNAPII arrest, this buffering system may fail locally, creating a topologically and architecturally constrained repair substrate. Here, we integrate established mechanisms of CSB-dependent RNAPII remodeling and recently defined ubiquitin-dependent clearance pathways with a testable model in which local torsional stress and topoisomerase-mediated relaxation influence repair permissiveness. In this framework, CSB remodels and organizes lesion-stalled RNAPII complexes, whereas topoisomerase may contribute to relaxation of transcription-generated supercoiling, thereby promoting a repair-permissive chromatin state. Recent evidence further indicates that CRL4^CSA-dependent RNAPII ubiquitylation initiates a hierarchical clearance program in which TFIIH/XPD drives rapid RNAPII displacement and VCP/p97 provides a backup extraction pathway. Together, these findings support a model in which TC-NER is possibly licensed not only by repair-factor recruitment but also by coordinated remodeling of RNAPII architecture, chromatin topology, and polymerase fate.