Break-induced replication is a source of mutation clusters underlying kataegis.
Break-induced replication is a source of mutation clusters underlying kataegis.
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DOI：
10.1016/j.celrep.2014.04.053
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发表时间：
2014-06-12
期刊：
影响因子：
8.8
通讯作者：
Malkova A
中科院分区：
文献类型：
--
作者：
Sakofsky CJ;Roberts SA;Malc E;Mieczkowski PA;Resnick MA;Gordenin DA;Malkova A
同时发生的多突变簇可能是癌变和进化过程中快速变化的一个来源。这种突变簇最近被证明起源于长单链DNA的DNA损伤，这些DNA是在被切除的双链断裂和功能失调的复制分叉处形成的。我们在这里发现双链断裂（DSB）诱导复制（BIR）是另一个强大的突变簇来源，在近一半的野生型酵母细胞中形成的BIR存在烷基化损伤。聚集突变主要沿着DNA合成的轨道形成，并且经常与额外的断裂和重排相关。此外，突变谱的碱基特异性、链配位性和链偏性与非常规复制中间体中持久性ssDNA延伸损伤引起的突变一致。总之，这些特征与癌症中的kataegic事件非常相似，表明BIR期间的复制中间体可能是跨物种突变簇的最突出来源。
Clusters of simultaneous multiple mutations can be a source of rapid change during carcinogenesis and evolution. Such mutation clusters have been recently shown to originate from DNA damage within long single-strand (ss) DNA formed at resected double-strand breaks and dysfunctional replication forks. We identify here double-strand break (DSB)-induced replication (BIR) as another powerful source of mutation clusters that formed in nearly half of wild-type yeast cells undergoing BIR in the presence of alkylating damage. Clustered mutations were primarily formed along the track of DNA synthesis and were frequently associated with additional breakage and rearrangements. Moreover, the base specificity, strand coordination and strand bias of the mutation spectrum was consistent with mutations arising from damage in persistent ssDNA stretches within unconventional replication intermediates. Together, these features closely resemble kataegic events in cancers, suggesting that replication intermediates during BIR may be the most prominent source of mutation clusters across species.
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