Lagging-strand replication shapes the mutational landscape of the genome.
Lagging-strand replication shapes the mutational landscape of the genome.
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DOI：
10.1038/nature14183
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发表时间：
2015-02-26
期刊：
影响因子：
64.8
通讯作者：
Taylor, Martin S.
中科院分区：
文献类型：
--
作者：
Reijns, Martin A. M.;Kemp, Harriet;Ding, James;de Proce, Sophie Marion;Jackson, Andrew P.;Taylor, Martin S.
突变的起源是理解进化的核心，也与健康有着关键的关系。变异在整个基因组中非随机发生，其机制仍有待确定。在这里，我们报告冈崎片段的5′-末端具有显著升高的核苷酸取代水平，表明此类突变的复制起源。通过一种新的方法emRiboSeq，我们绘制了聚合酶的全基因组贡献，并表明尽管Okazaki片段加工，但由易错Pol-α合成的DNA保留在体内，占成熟基因组的约1.5%。我们认为，DNA结合蛋白在复制后迅速重新结合，作为Pol-δ介导的Pol-α合成DNA置换的部分屏障，导致此类Pol-α片段的掺入和特定位点突变率的升高。我们观察到染色质和调控蛋白结合的突变成本，导致调控元件的突变热点，在酵母和人类中都可以检测到这个过程的签名。
The origin of mutations is central to understanding evolution and of key relevance to health. Variation occurs non-randomly across the genome, and mechanisms for this remain to be defined. Here, we report that the 5′-ends of Okazaki fragments have significantly elevated levels of nucleotide substitution, indicating a replicative origin for such mutations. With a novel method, emRiboSeq, we map the genome-wide contribution of polymerases, and show that despite Okazaki fragment processing, DNA synthesised by error-prone Pol-α is retained in vivo, comprising ~1.5% of the mature genome. We propose that DNA-binding proteins that rapidly re-associate post-replication act as partial barriers to Pol-δ mediated displacement of Pol-α synthesised DNA, resulting in incorporation of such Pol-α tracts and elevated mutation rates at specific sites. We observe a mutational cost to chromatin and regulatory protein binding, resulting in mutation hotspots at regulatory elements, with signatures of this process detectable in both yeast and humans.
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影响因子：
16
作者：
Ghodgaonkar, Medini Manohar;Lazzaro, Federico;Olivera-Pimentel, Maite;Artola-Boran, Mariela;Cejka, Petr;Reijns, Martin A.;Jackson, Andrew P.;Plevani, Paolo;Muzi-Falconi, Marco;Jiricny, Josef
通讯作者：
Jiricny, Josef
影响因子：
4.5
作者：
Miyabe I;Kunkel TA;Carr AM
通讯作者：
Carr AM
影响因子：
14.9
作者：
Chon H;Sparks JL;Rychlik M;Nowotny M;Burgers PM;Crouch RJ;Cerritelli SM
通讯作者：
Cerritelli SM
影响因子：
4
作者：
Alexandrov, Ludmil B.;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
影响因子：
5.3
作者：
KUNKEL, TA;HAMATAKE, RK;SUGINO, A
通讯作者：
SUGINO, A