The NER Structure-specific ERCC1-XPF Endonuclease Heterodimer Cooperates with DNA Topoisomerase II for the Repair of Transcription-associated DNA Breaks

Transcription is a potential threat to genome integrity and transcription-associated DNA damage must rapidly be repaired for proper mRNA synthesis. For a wide range of structurally diverse DNA lesions, cells employ the highly conserved nucleotide excision repair (NER) pathway to restore their genome back to its native form. Recent evidence suggests that NER factors function, in addition to the canonical DNA repair mechanism, in processes that facilitate mRNA synthesis or shape the 3D chromatin architecture. Using an in vivo biotinylation tagging approach in mice coupled to high-throughput genomics and proteomics approaches, we show that ERCC1-XPF acts synergistically with the DNA Topoisomerase II to relieve the DNA topological stress associated with the process of mRNA synthesis. Specifically, we find that the heterodimer interacts with Topoisomerase IIβ and that, upon transcription stimulation, it binds preferentially to promoters marked with DSBs; interestingly, we find that the endonuclease complex is released upon UV-induced DNA damage repair. We propose that ERCC1-XPF is functionally associated with the repair of transcription-associated DNA damage events, shedding new light into the enormous heterogeneity associated with NER-deficient syndromes.