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Emerging evidence suggests that sublethal apoptotic signaling may contribute to structural genome remodeling. Oxidative stress and inflammatory stimuli trigger caspase activation and the release of caspase-activated DNase (CAD), which preferentially cleaves DNA at matrix association regions\/scaffold attachment regions (MAR\/SARs) that anchor chromatin loops to the nuclear scaffold. When apoptotic execution is incomplete and cells undergo recovery, a process termed anastasis, CAD-induced double-strand breaks (DSBs) can be repaired through error-prone end-joining pathways, including classical non-homologous end joining (cNHEJ) and microhomology-mediated end joining (MMEJ), producing rearrangements enriched at MAR\/SAR-associated genomic regions. Drawing on mechanistic studies in leukemia and experimental evidence in nasopharyngeal carcinoma (NPC), this review outlines a framework linking apoptotic DNA fragmentation, nuclear architecture, and error-prone repair to recurrent structural variations, and discusses how shared inflammation- and virus-associated oxidative stress may promote analogous mechanisms of breakpoint formation in other malignancies. The convergence of findings across hematologic and epithelial malignancies strengthens the biological plausibility and potential generalizability of this model across inflammation- and stress-associated cancers. This perspective suggests that at least a subset of cancer-associated chromosomal rearrangements may arise not purely as stochastic by-products of genomic instability, but as structured outcomes of dysregulated cell-death programs acting on vulnerable chromatin domains. Beyond its mechanistic implications, this framework may inform biomarker discovery through apoptosis-associated breakpoint features and highlight potential therapeutic vulnerabilities in apoptosis-surviving cells, including dependence on polymerase theta-mediated repair or regulation of apoptotic execution.<\/jats:p>","DOI":"10.1038\/s41389-026-00645-x","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T22:12:35Z","timestamp":1784931155000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Apoptosis-driven chromosomal rearrangements in cancer: CAD cleavage, nuclear architecture, and microhomology-mediated end joining"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1223-0623","authenticated-orcid":false,"given":"Sang-Nee","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"645_CR1","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1091\/mbc.e11-11-0926","volume":"23","author":"HL Tang","year":"2012","unstructured":"Tang HL, Tang HM, Mak KH, Hu S, Wang SS, Wong KM, et al. 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