Replication stress activates DNA repair synthesis in mitosis
Replication stress activates DNA repair synthesis in mitosis
复制标题
复制应激激活有丝分裂中的 DNA 修复合成
DOI：
10.1038/nature16139
复制
发表时间：
2015-12-10
期刊：
影响因子：
64.8
通讯作者：
Hickson, Ian D.
中科院分区：
文献类型：
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作者：
Minocherhomji, Sheroy;Ying, Songmin;Hickson, Ian D.
癌基因诱导的DNA复制应激已被认为是肿瘤发生的驱动因素。许多人类癌症特有的染色体重排起源于基因组中被称为共同脆性位点（CFS）的特定区域。CFS是难以复制的基因座，表现为中期染色体上的缺口或断裂（称为CFS“表达”），特别是当细胞暴露于复制应激时。MUS 81-EME 1结构特异性核酸内切酶促进复制应激后CFSs处染色体间隙或断裂的出现。在这里，我们表明，进入有丝分裂前期的细胞触发招聘的MUS 81 CFSs。然后，MUS 81的核酸酶活性促进CFS处的POLD 3依赖性DNA合成，这用于使染色体错误分离和不分离最小化。我们建议，在早期有丝分裂的不完全重复的位点的尝试冷凝作为触发完成在CFS基因座在人类细胞中的DNA复制。鉴于这种POLD 3依赖性有丝分裂DNA合成在表现出固有高水平的染色体不稳定性（CIN+）和复制应激的非整倍体癌细胞中增强，我们建议靶向该途径可能代表一种新的治疗方法。
Oncogene-induced DNA replication stress has been implicated as a driver of tumorigenesis. Many chromosomal rearrangements characteristic of human cancers originate from specific regions of the genome called common fragile sites (CFSs),,,. CFSs are difficult-to-replicate loci that manifest as gaps or breaks on metaphase chromosomes (termed CFS ‘expression’), particularly when cells have been exposed to replicative stress. The MUS81–EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSs following replicative stress,,. Here we show that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which serves to minimize chromosome mis-segregation and non-disjunction. We propose that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN+) and replicative stress, we suggest that targeting this pathway could represent a new therapeutic approach.