Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.
Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.
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DOI：
10.1101/gr.174789.114
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发表时间：
2014-11
期刊：
影响因子：
7
通讯作者：
Wheeler DA
中科院分区：
文献类型：
--
作者：
Shinbrot E;Henninger EE;Weinhold N;Covington KR;Göksenin AY;Schultz N;Chao H;Doddapaneni H;Muzny DM;Gibbs RA;Sander C;Pursell ZF;Wheeler DA
在DNA聚合酶E3的校正核酸外切酶结构域（POLE-exo*）中具有体细胞突变的肿瘤表现出一种新的增变基因表型，TCT→达特和TCG→TTG突变显著升高，总体突变频率通常超过100个突变/Mb。在这里，我们在许多癌症中鉴定出POLE-exo* 肿瘤，并根据其突变特性将其分为两组，A和B。A组突变体仅在POLE中发现，而B组突变体在POLE和POLD 1中发现，并且似乎是无功能的。在A组中，无细胞聚合酶测定证实核酸外切酶结构域中的突变导致高突变频率，优先发生C→A突变。我们描述了由POLE-exo* 引起的氨基酸取代的模式，并将其与其他肿瘤类型进行比较。POLE-exo* 的核苷酸偏好导致关键肿瘤抑制因子如TP 53、ATM和PIK 3R 1中复发性无义突变的频率增加。我们进一步证明，链特异性突变模式出现从一些这些POLE-exo* 突变体在基因组复制。这是人类POLE的前导链特异性复制的第一个直接证据，到目前为止，这只在酵母中得到证实。总之，极高的突变频率和突变的链特异性提供了真核生物复制起点的唯一标识符。
Tumors with somatic mutations in the proofreading exonuclease domain of DNA polymerase epsilon (POLE-exo*) exhibit a novel mutator phenotype, with markedly elevated TCT→TAT and TCG→TTG mutations and overall mutation frequencies often exceeding 100 mutations/Mb. Here, we identify POLE-exo* tumors in numerous cancers and classify them into two groups, A and B, according to their mutational properties. Group A mutants are found only in POLE, whereas Group B mutants are found in POLE and POLD1 and appear to be nonfunctional. In Group A, cell-free polymerase assays confirm that mutations in the exonuclease domain result in high mutation frequencies with a preference for C→A mutation. We describe the patterns of amino acid substitutions caused by POLE-exo* and compare them to other tumor types. The nucleotide preference of POLE-exo* leads to increased frequencies of recurrent nonsense mutations in key tumor suppressors such as TP53, ATM, and PIK3R1. We further demonstrate that strand-specific mutation patterns arise from some of these POLE-exo* mutants during genome duplication. This is the first direct proof of leading strand-specific replication by human POLE, which has only been demonstrated in yeast so far. Taken together, the extremely high mutation frequency and strand specificity of mutations provide a unique identifier of eukaryotic origins of replication.
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常见的与癌症相关的DNA聚合酶ε突变会导致异常强的突变器表型，表明富达缺陷与校对丧失不同。
影响因子：
11.2
作者：
Kane DP;Shcherbakova PV
通讯作者：
Shcherbakova PV
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.5
作者：
Miyabe I;Kunkel TA;Carr AM
通讯作者：
Carr AM
影响因子：
16.8
作者：
Hogg, Matthew;Osterman, Pia;Johansson, Erik
通讯作者：
Johansson, Erik
影响因子：
3.5
作者：
Church DN;Briggs SE;Palles C;Domingo E;Kearsey SJ;Grimes JM;Gorman M;Martin L;Howarth KM;Hodgson SV;NSECG Collaborators;Kaur K;Taylor J;Tomlinson IP
通讯作者：
Tomlinson IP