Flap endonuclease 1 repairs DNA-protein cross-links via ADP-ribosylation–dependent mechanisms

DNA-protein cross-links (DPCs) are among the most detrimental genomic lesions. They are ubiquitously produced by formaldehyde (FA), and failure to repair FA-induced DPCs blocks chromatin-based processes, leading to neurodegeneration and cancer. The type, structure, and repair of FA-induced DPCs remain largely unknown. Here, we profiled the proteome of FA-induced DPCs and found that flap endonuclease 1 (FEN1) resolves FA-induced DPCs. We revealed that FA also damages DNA bases adjoining the DPCs, leading to DPC-conjugated 5' flap structures via the base excision repair (BER) pathway. We also found that FEN1 repairs enzymatic topoisomerase II (TOP2)-DPCs. Furthermore, we report that both FA-induced and TOP2-DPCs are adenosine diphosphate (ADP) ribosylated by poly(ADP-ribose) polymerase 1 (PARP1). PARylation of the DPCs in association with FEN1 PARylation at residue E285 is required for the recruitment of FEN1. Our work unveils the identity of proteins forming FA-induced DPCs and a previously unrecognized PARP1-FEN1 nuclease pathway repairing both FA- and TOP2-DPCs.

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Publication Details

Journal
Science Advances
Published
2025-01-10
DOI
https://doi.org/10.1126/sciadv.ads2919
Citations
7
Primary Topic
Cancer therapeutics and mechanisms
Type
article
Field-Weighted Citation Impact
5.64

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article

Flap endonuclease 1 repairs DNA-protein cross-links via ADP-ribosylation–dependent mechanisms

Linying Zhu, Lara H. El Touny, Lisa M. Miller Jenkins, Xi Yang et al.
7 citations
Science Advances
Cancer therapeutics and mechanisms
5.64
article

Flap endonuclease 1 repairs DNA-protein cross-links via ADP-ribosylation–dependent mechanisms

Linying Zhu, Lara H. El Touny, Lisa M. Miller Jenkins, Xi Yang, Ukhyun Jo, Shunichi Takeda, Anthony K. L. Leung, Liton Kumar Saha, Yves Pommier, Yilun Sun, Tapan Kumar Maity, Ken Chih-Chien Cheng, Isabel Uribe, Lauren Escobedo, Sourav Saha
article en
7 citations

Abstract

DNA-protein cross-links (DPCs) are among the most detrimental genomic lesions. They are ubiquitously produced by formaldehyde (FA), and failure to repair FA-induced DPCs blocks chromatin-based processes, leading to neurodegeneration and cancer. The type, structure, and repair of FA-induced DPCs remain largely unknown. Here, we profiled the proteome of FA-induced DPCs and found that flap endonuclease 1 (FEN1) resolves FA-induced DPCs. We revealed that FA also damages DNA bases adjoining the DPCs, leading to DPC-conjugated 5' flap structures via the base excision repair (BER) pathway. We also found that FEN1 repairs enzymatic topoisomerase II (TOP2)-DPCs. Furthermore, we report that both FA-induced and TOP2-DPCs are adenosine diphosphate (ADP) ribosylated by poly(ADP-ribose) polymerase 1 (PARP1). PARylation of the DPCs in association with FEN1 PARylation at residue E285 is required for the recruitment of FEN1. Our work unveils the identity of proteins forming FA-induced DPCs and a previously unrecognized PARP1-FEN1 nuclease pathway repairing both FA- and TOP2-DPCs.

Science AdvancesVol. 11(2)
University of Maryland, Baltimore (US), Johns Hopkins University (US), Shenzhen University (CN), National Cancer Institute (US), National Center for Advancing Translational Sciences (US), Center for Cancer Research (US), University of Baltimore (US)
National Cancer Institute
Openalex Percentile: Top 4%
Cancer therapeutics and mechanisms
5.64
DOIOpen Access PDFOpenAlex
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