{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:06:32Z","timestamp":1789103192138,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Replication stress (RS) represents a major vulnerability of cancer cells treated with nucleoside analogs and related antimetabolites; however, tumors frequently acquire tolerance mechanisms that permit survival despite persistent DNA lesions. This review examines molecular determinants of RS tolerance, focusing on human T-cell leukemia virus type 1 (HTLV-1)-mediated adult T-cell leukemia\/lymphoma (ATL) as a model of virus-mediated rewiring of DNA damage responses. Chain-terminating nucleoside analogs generate aberrant replication intermediates, including blocked 3\u2019 DNA termini, mis-incorporated bases, and stalled replication forks. In ATL, viral oncoproteins suppress key components of replication stress response pathways, notably tyrosyl-DNA phosphodiesterase 1 (TDP1) and mismatch repair (MMR), thereby creating exploitable repair deficiencies. Consistent with this vulnerability, ATL cells exhibit marked sensitivity to replication stress\u2013inducing agents such as irinotecan (CPT-11) and the chain-terminating nucleoside analog abacavir. Recent CRISPR-based functional genomics studies further identify Schlafen 11 (SLFN11) as an independent and dominant regulator of RS sensitivity. SLFN11 determines the fate of stressed replication forks independently of lesion processing, acting as an execution factor that converts otherwise tolerable RS into irreversible replication arrest. We conclude by discussing therapeutic strategies that exploit RS tolerance defects in ATL, including biomarker-guided nucleoside analog therapy, and rational combination approaches targeting compensatory RS pathways.<\/jats:p>","DOI":"10.3390\/biom16091310","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:43:16Z","timestamp":1788972196000},"page":"1310","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Replication Stress Tolerance in Adult T-Cell Leukemia"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9515-8139","authenticated-orcid":false,"given":"Yusuke","family":"Okamoto","sequence":"first","affiliation":[{"name":"Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto 606-8303, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-8458","authenticated-orcid":false,"given":"Masayuki","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto 606-8303, Japan"},{"name":"Department of Hematology, Japan Baptist Hospital, Kyoto 606-8273, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8868-1661","authenticated-orcid":false,"given":"Takashi","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto 606-8303, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7469-1276","authenticated-orcid":false,"given":"Kotaro","family":"Shirakawa","sequence":"additional","affiliation":[{"name":"Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto 606-8303, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7678-4284","authenticated-orcid":false,"given":"Akifumi","family":"Takaori-Kondo","sequence":"additional","affiliation":[{"name":"Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto 606-8303, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nrc3916","article-title":"Replication stress and cancer","volume":"15","author":"Gaillard","year":"2015","journal-title":"Nat. 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