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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.<\/jats:p>","DOI":"10.1126\/sciadv.adu0437","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T13:58:56Z","timestamp":1744811936000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":22,"title":["Mechanism of DNA replication fork breakage and PARP1 hyperactivation during replication catastrophe"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4216-3695","authenticated-orcid":true,"given":"Pedro","family":"Ortega","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA."},{"name":"Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, 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