Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions.
Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions.
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DOI：
10.1016/j.molcel.2012.03.030
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发表时间：
2012-05-25
期刊：
影响因子：
16
通讯作者：
Gordenin, Dmitry A.
中科院分区：
文献类型：
--
作者：
Roberts, Steven A.;Sterling, Joan;Thompson, Cole;Harris, Shawn;Mav, Deepak;Shah, Ruchir;Klimczak, Leszek J.;Kryukov, Gregory V.;Malc, Ewa;Mieczkowski, Piotr A.;Resnick, Michael A.;Gordenin, Dmitry A.
突变通常被视为随机、独立的事件。我们在这里描述了酵母和人类癌症中的非随机聚集突变。对在慢性烷基化损伤下生长的酵母进行基因组测序，发现了长达 200 kb 的突变簇。同一链中胞嘧啶或鸟嘌呤的“链协调”变化、突变模式和遗传控制占主导地位，表明在双链断裂 (DSB) 和复制叉处形成的异常长单链 (ss) DNA 中的碱基烷基化会产生同时突变。值得注意的是，我们在测序的人类癌症中发现了具有类似特征的突变簇。突变胞嘧啶或鸟嘌呤的链协调簇通常位于染色体重排断点附近，并且高度富集 APOBEC 家族胞嘧啶脱氨酶靶向的基序，该基序强烈偏爱 ssDNA。这些数据表明，随机形成的 ssDNA 中多个同时变化引起的超突变是一种普遍现象，可能是产生快速遗传变异的重要机制。
Mutations are typically perceived as random, independent events. We describe here non-random clustered mutations in yeast and in human cancers. Genome sequencing of yeast grown under chronic alkylation damage identified mutation clusters that extend up to 200 kb. A predominance of “strand-coordinated” changes of either cytosines or guanines in the same strand, mutation patterns and genetic controls indicated that simultaneous mutations were generated by base alkylation in abnormally long single-strand (ss)DNA formed at double-strand breaks (DSBs) and replication forks. Significantly, we found mutation clusters with analogous features in sequenced human cancers. Strand-coordinated clusters of mutated cytosines or guanines often resided near chromosome rearrangement breakpoints and were highly enriched with a motif targeted by APOBEC family cytosine-deaminases, which strongly prefer ssDNA. These data indicate that hyper-mutation via multiple simultaneous changes in randomly formed ssDNA is a general phenomenon that may be an important mechanism producing rapid genetic variation.
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影响因子：
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DOI：
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