PARP1 regulates the genomic ribonucleotide processing activity of TOP1 to prevent the formation of toxic TOP1-DNA adducts and the associated mutations
Year: 2026
Type: preprint
Abstract: Ribonucleotides are frequently incorporated into the genome during DNA replication and are normally removed by RNase H2. Alternatively, DNA topoisomerase 1 (TOP1) can process genomic ribonucleotides through two sequential cleavage events, generating a 2',3'-cyclic phosphate-terminated nick and, subsequently, a TOP1 cleavage complex (TOP1cc). In addition, TOP1cc formation can lead to 2- to 5-bp slippage deletions, recently identified as the ID4 cancer signature. Here, we show that human TOP1 is intrinsically mutagenic, with a tendency to undergo secondary cleavage and form TOP1 cleavage complexes. We further demonstrate that PARP1, a central single-strand break repair factor, suppresses TOP1 secondary cleavage, TOP1cc formation, and the resulting slippage mutations. This regulation requires PARP1 to interact with both TOP1 and the 2',3'-cyclic phosphate-terminated nick produced by the initial TOP1 cleavage. Notably, a PARP1 mutant defective in TOP1 interaction is partially impaired in restoring PARP inhibitor sensitivity in PARP1-knockout cells, suggesting that PARP inhibitor cytotoxicity may partly result from PARP1 trapping at 2',3'-cyclic phosphate-terminated nicks and blocking their processing by TOP1 and other factors. Together, these findings reveal a novel role for PARP1 in regulating TOP1-dependent ribonucleotide processing, thereby suppressing cancer-signature mutations and contributing to the mechanism of PARP inhibitor cytotoxicity.
Authors: Edward James Sarrain, Quan Wang, Angel Caitlin Bondoy, Feng Guo, Qi Cao, Hengyao Niu
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Topoisomerase 1-catalyzed genomic ribonucleotide excision, its regulation, and its implication in transcription., A novel role for EZH2 in PARP regulation and PARPi-resistance in prostate cancer, A novel role for EZH2 in A-to-I RNA editing in prostate cancer, A non-canonical role for EZH2 in rRNA methtlation, SPORE in Prostate Cancer, Mechanism and Regulation of Homologous Recombination in Genome Maintenance, Combinational targeting histone and RNA modifications in prostate cancer
OpenAlex ID: W7155079730