研究团队描述了这种重编程的机制：ATP酶TTF2被招募到复制体，其非催化性N端结构域将细胞周期蛋白B-CDK1磷酸化的TRAIP以一种允许复制体泛素化的几何形状连接到前导链DNA聚合酶ε上。因此，在有丝分裂过程中，一个磷酸化调控的结构开关改变了复制体的组织，从而在染色体分离之前保护了基因组的完整性。
研究人员表示，DNA复制不完全进入有丝分裂的细胞面临灾难性的染色体分离失败。在间期，复制体相关的E3泛素连接酶TRAIP泛素化分叉前的屏障，以允许复制体进展。在有丝分裂中，TRAIP被重新编程，从一个反式作用的连接酶变成一个顺式作用的连接酶，它可以使复制体本身泛素化。这使得未复制DNA的加工能够通过促进复制体的分解、分叉断裂和断裂染色体臂的连接来实现。
附：英文原文
Title: A CDK1 phospho-switch reprograms TRAIP to unload replisomes in mitosis
Author: Geylani Can, Maksym Shyian, Archana Krishnamoorthy, Samreen Ahmed, Yang Lim, Alex Wu, Raphael Pavani, Manal S. Zaher, André Nussenzweig, Markus Rschle, Thomas E. Wilson, Thomas W. Glover, Johannes C. Walter, David Pellman
Issue&Volume: 2026-07-02
Abstract: 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 ATPase TTF2 is recruited to the replisome, where its noncatalytic N-terminal domain tethers Cyclin B-CDK1-phosphorylated TRAIP to the leading strand DNA polymerase ε in a geometry that allows replisome ubiquitylation. Thus, a phospho-regulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.
DOI: aeh1834
Source: https://www.science.org/doi/10.1126/science.aeh1834