Mechanism of DNA replication fork breakage and PARP1 hyperactivation during replication catastrophe Journal Article

  


Authors: Ortega, P.; Bournique, E.; Li, J.; Sanchez, A.; Santiago, G.; Harris, B. R.; Striepen, J.; Maciejowski, J.; Green, A. M.; Buisson, R.
Article Title: Mechanism of DNA replication fork breakage and PARP1 hyperactivation during replication catastrophe
Abstract: Ataxia telangiectasia and Rad3-related (ATR) inhibition triggers a surge in origin firing, resulting in increased levels of single-stranded DNA (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected and susceptible to breakage, a phenomenon known as replication catastrophe. However, the mechanism by which unprotected ssDNA breaks remains unclear. Here, we reveal that APOBEC3B is the key enzyme targeting unprotected ssDNA at replication forks, initiating a reaction cascade that induces fork collapse and poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Mechanistically, we demonstrate that uracils generated by APOBEC3B at replication forks are removed by UNG2, resulting in abasic sites that are subsequently cleaved by APE1 endonuclease. Moreover, we show that APE1-mediated DNA cleavage is the critical enzymatic step for PARP1 hyperactivation in cells, regardless of how abasic sites are generated on DNA. Last, we demonstrate that APOBEC3B-induced PARP1 trapping and DNA double-strand breaks drive cell sensitivity to ATR inhibition, creating a context of synthetic lethality when coupled with PARP inhibitors. Copyright © 2025 The Authors, some rights reserved.
Keywords: dna cleavage; ataxia telangiectasia; replication fork; endonucleases; dna breaks; hyperactivation; economic and social effects; dna replication forks; key enzymes; poly(adp ribose) polymerase 1; reaction cascades
Journal Title: Science Advances
Volume: 11
Issue: 16
ISSN: 2375-2548
Publisher: Amer Assoc Advancement Science  
Date Published: 2025-04-18
Start Page: eadu0437
Language: English
DOI: 10.1126/sciadv.adu0437
PROVIDER: scopus
PUBMED: 40238882
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-105003217426&doi=10.1126%2fsciadv.adu0437&partnerID=40&md5=645ec7bb43614b6dee1416037b0e3836
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus
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MSK Authors
  1. John Maciejowski
    32 Maciejowski
  2. Josefine Ursel Striepen
    5 Striepen
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