Gillespie Peter J, Blow J Julian
Centre for Gene Regulation & Expression, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Biology (Basel). 2022 Jun 7;11(6):877. doi: 10.3390/biology11060877.
The maintenance of genomic stability during the mitotic cell-cycle not only demands that the DNA is duplicated and repaired with high fidelity, but that following DNA replication the chromatin composition is perpetuated and that the duplicated chromatids remain tethered until their anaphase segregation. The coordination of these processes during S phase is achieved by both cyclin-dependent kinase, CDK, and Dbf4-dependent kinase, DDK. CDK orchestrates the activation of DDK at the G1-to-S transition, acting as the 'global' regulator of S phase and cell-cycle progression, whilst 'local' control of the initiation of DNA replication and repair and their coordination with the re-formation of local chromatin environments and the establishment of chromatid cohesion are delegated to DDK. Here, we discuss the regulation and the multiple roles of DDK in ensuring chromosome maintenance. Regulation of replication initiation by DDK has long been known to involve phosphorylation of MCM2-7 subunits, but more recent results have indicated that Treslin:MTBP might also be important substrates. Molecular mechanisms by which DDK regulates replisome stability and replicated chromatid cohesion are less well understood, though important new insights have been reported recently. We discuss how the 'outsourcing' of activities required for chromosome maintenance to DDK allows CDK to maintain outright control of S phase progression and the cell-cycle phase transitions whilst permitting ongoing chromatin replication and cohesion establishment to be completed and achieved faithfully.
在有丝分裂细胞周期中维持基因组稳定性，不仅要求DNA以高保真度进行复制和修复，还要求在DNA复制后染色质组成得以延续，并且复制后的染色单体保持连接状态，直到后期分离。在S期，细胞周期蛋白依赖性激酶（CDK）和Dbf4依赖性激酶（DDK）共同实现了这些过程的协调。CDK在G1期到S期的转换过程中协调DDK的激活，作为S期和细胞周期进程的“全局”调节因子，而DNA复制和修复起始的“局部”控制以及它们与局部染色质环境重新形成和染色单体黏连建立的协调则由DDK负责。在这里，我们讨论DDK在确保染色体维持方面的调节作用和多种功能。长期以来已知DDK对复制起始的调节涉及MCM2-7亚基的磷酸化，但最近的结果表明Treslin:MTBP可能也是重要的底物。尽管最近有重要的新见解报道，但DDK调节复制体稳定性和复制染色单体黏连的分子机制仍不太清楚。我们讨论了将染色体维持所需的活动“外包”给DDK如何使CDK能够全面控制S期进程和细胞周期阶段转换，同时确保正在进行的染色质复制和黏连建立得以忠实地完成。
