Mcm10 deficiency causes defective-replisome-induced mutagenesis and a dependency on error-free postreplicative repair
Mcm10 deficiency causes defective-replisome-induced mutagenesis and a dependency on error-free postreplicative repair
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DOI：
10.4161/cc.28652
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发表时间：
2014-06-01
期刊：
影响因子：
4.3
通讯作者：
Bielinsky, Anja-Katrin
中科院分区：
文献类型：
--
作者：
Becker, Jordan R.;Hai Dang Nguyen;Bielinsky, Anja-Katrin
mcm 10是一种多功能复制因子，据报道在起始激活、聚合酶加载和复制叉进展中起作用。文献支持这些变量的作用是有争议的，它一直在争论是否Mcm 10有一个积极的作用，在延长。在这里，我们提供了证据表明mcm 10 -1等位基因会改变DNA合成，从而导致缺陷复制体诱导的突变（DRIM）。具体来说，我们观察到，mcm 10 -1细胞表现出水平升高的PCNA泛素化和激活的translesion聚合酶，pol-zeta。而translesion合成有没有可测量的影响的生存能力，mcm 10 -1突变体也从事无错误的复制后修复（PRR），这一途径促进生存在半许可条件。mcm 10 -1中的复制缺口可能是由延伸缺陷引起的，因为dbf 4 -1突变体，其对起始点激活的损害没有显示任何复制应激的标志。此外，我们证明，引发的缺陷，由pol 1 -1突变引起的，也导致DRIM，但不是在无错误的PRR。与mcm 10 -1突变体相似，DRIM不能挽救pol 1 -1细胞中的复制缺陷。因此，DRIM似乎不擅长填补pol 1 -1和mcm 10 -1突变体中的复制缺口。此外，正确引发新生DNA的能力可能是启动无错误PRR的关键先决条件。
Mcm10 is a multifunctional replication factor with reported roles in origin activation, polymerase loading, and replication fork progression. The literature supporting these variable roles is controversial, and it has been debated whether Mcm10 has an active role in elongation. Here, we provide evidence that the mcm10-1 allele confers alterations in DNA synthesis that lead to defective-replisome-induced mutagenesis (DRIM). Specifically, we observed that mcm10-1 cells exhibited elevated levels of PCNA ubiquitination and activation of the translesion polymerase, pol-zeta. Whereas translesion synthesis had no measurable impact on viability, mcm10-1 mutants also engaged in error-free postreplicative repair (PRR), and this pathway promoted survival at semi-permissive conditions. Replication gaps in mcm10-1 were likely caused by elongation defects, as dbf4-1 mutants, which are compromised for origin activation did not display any hallmarks of replication stress. Furthermore, we demonstrate that deficiencies in priming, induced by a pol1-1 mutation, also resulted in DRIM, but not in error-free PRR. Similar to mcm10-1 mutants, DRIM did not rescue the replication defect in pol1-1 cells. Thus, it appears that DRIM is not proficient to fill replication gaps in pol1-1 and mcm10-1 mutants. Moreover, the ability to correctly prime nascent DNA may be a crucial prerequisite to initiate error-free PRR.