A CDK1 phospho-switch reprograms TRAIP to unload replisomes in mitosis

• 成果类型: Article
• 署名作者: Can, Geylani; Shyian, Maksym; Krishnamoorthy, Archana; Ahmed, Samreen; Lim, Yang; Wu, Alex; Pavani, Raphael; Zaher, Manal S.; Nussenzweig, Andre; Raschle, Markus; Wilson, Thomas E.; Glover, Thomas W.; Walter, Johannes C.; Pellman, David
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); RPTU University Kaiserslautern; Howard Hughes Medical Institute; Washington University (WUSTL)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aeh1834
• 发表日期: 2026-08-13
• 页码: eaeh1834
• 关键词: dna-replication; genome-wide; termination; initiation; RESOLUTION; mechanism; chromatin; resection; BREAKAGE; helicase

摘要

Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a trans-acting to a cis-acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: The adenosine triphosphatase transcription termination factor 2 (TTF2) is recruited to the replisome, where its noncatalytic N-terminal domain tethers cyclin B-cyclin-dependent kinase 1-phosphorylated TRAIP to the leading strand DNA polymerase epsilon in a geometry that allows replisome ubiquitylation. Thus, a phosphoregulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.