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However, efficient repair or suppression of ssDNA gap formation is associated with therapy resistance and treatment failure. Therefore, understanding how ssDNA gaps form and are repaired can help identify biomarkers that can guide new treatment strategies to overcome resistance. In this review, we discuss different sources of ssDNA gap formation and the repair mechanisms that have been characterized to date. We bring together current knowledge on how these gaps are processed and what their ultimate fate may be. Finally, we discuss how established drugs like PARPi, hydroxyurea, and platinum compounds, induce and\/or exploit ssDNA gaps. Throughout this review, we highlight ssDNA gaps as a potential therapeutic vulnerability that can be used to advance personalized cancer therapy.<\/jats:p>","DOI":"10.1042\/bcj20253455","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T07:51:41Z","timestamp":1774943501000},"page":"527-540","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Understanding single stranded DNA gaps: from formation to fate"],"prefix":"10.1042","volume":"483","author":[{"given":"Sonal","family":"Garg","sequence":"first","affiliation":[{"name":"Department of Molecular and Precision Medicine, The Pennsylvania State University College of Medicine, Hershey, PA 17033, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3825-149X","authenticated-orcid":false,"given":"George-Lucian","family":"Moldovan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Precision Medicine, The Pennsylvania State University College of Medicine, Hershey, PA 17033, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"2026033103513728000_B1","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1101\/gad.234070.113","article-title":"The yeast and human FACT chromatin-reorganizing complexes solve R-loop-mediated transcription-replication conflicts","volume":"28","author":"Herrera-Moyano","year":"2014","journal-title":"Genes Dev."},{"key":"2026033103513728000_B2","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1016\/j.cell.2011.04.015","article-title":"DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase","volume":"145","author":"Paeschke","year":"2011","journal-title":"Cell"},{"key":"2026033103513728000_B3","doi-asserted-by":"publisher","first-page":"5723","DOI":"10.1021\/bi00342a006","article-title":"Cyclobutane pyrimidine dimers and (6-4) photoproducts block polymerization by DNA polymerase I","volume":"24","author":"Chan","year":"1985","journal-title":"Biochemistry"},{"key":"2026033103513728000_B4","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1016\/j.cell.2008.08.030","article-title":"Mechanism of replication-coupled DNA interstrand crosslink repair","volume":"134","author":"R\u00e4schle","year":"2008","journal-title":"Cell"},{"key":"2026033103513728000_B5","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/0092-8674(92)90593-2","article-title":"A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia","volume":"71","author":"Kastan","year":"1992","journal-title":"Cell"},{"key":"2026033103513728000_B6","doi-asserted-by":"publisher","first-page":"13741","DOI":"10.1074\/jbc.274.20.13741","article-title":"Role of DNA polymerase beta in the excision step of long patch mammalian base excision repair","volume":"274","author":"Dianov","year":"1999","journal-title":"J. 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