RNAPII and XPC remodel the 3D genome for UV repair
Year: 2026
Type: preprint
Abstract: The three-dimensional (3D) genome architecture is highly elastic, adapting to nuclear processes such as transcription and the DNA damage response 1,2 . Nucleotide excision repair (NER) acts within this chromatin context to detect and repair mutagenic lesions induced by ultraviolet (UV) irradiation 3 . UV irradiation has been shown to induce restructuring of the 3D genome across multiple scales, including chromatin compartments, domains, and loops. However, the extent to which NER activity contributes to this remodelling remains unresolved, as the only prior study tracking such UV-induced changes was limited to repair-proficient cells 4 . Here, by combining genome-wide chromatin profiling of repair-deficient human cells with loop extrusion simulations, we show that the transcription-coupled NER initiator RNA polymerase II (RNAPII) and the global-genome NER initiator Xeroderma pigmentosum group C (XPC) each constrain loop extrusion upon UV irradiation. These events counter the loop-lengthening effects of UV-induced transcriptional shutdown, leading to shorter chromatin loops and reinforced chromatin domains that facilitate efficient lesion recognition and repair. The contribution by RNAPII extends its role beyond activating transcription-coupled repair to promoting a genome-wide repair-permissive state. The contribution by XPC establishes 3D genome reorganisation as an active mechanism both initiated and harnessed by DNA repair, rather than a passive consequence of DNA damage. Together, these findings advance our understanding of how nuclear processes coordinate on and alter a shared chromatin substrate to preserve genome integrity.
Institutions: Sabancı Üniversitesi, University of Zurich
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7166177273