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Publications

Journal Article Ppublish 8 citations

PubMed: 39792662 DOI: 10.1126/sciadv.ads2919

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

Sci Adv 11(2):eads2919

Authors: Yilun Sun, Lisa M Jenkins, Lara H El Touny, Linying Zhu, Xi Yang, Ukhyun Jo, Lauren Escobedo, Tapan K Maity, Liton Kumar Saha, Isabel Uribe, Sourav Saha, Shunichi Takeda, Anthony K L Leung, Ken Cheng, Yves Pommier

Affiliations

  • Department of Pharmacology, Physiology and Drug Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • University of Maryland Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, Baltimore, MD 21201, USA.
  • Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
  • Mass Spectrometry Section, Collaborative Protein Technology Resource, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
  • Function Genomics Laboratory, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
  • Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Shenzhen University School of Medicine, Shenzhen, Guangdong, China.

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.

MeSH

Adp-Ribosylation, Poly(Adp-Ribose) Polymerases, Biological Science Disciplines, Poly Adenosine Diphosphate Ribose, Flap Endonucleases, Dna, Endonucleases, Excision Repair