Mutagenic mechanisms of cancer-associated DNA polymerase ϵ alleles.
Mutagenic mechanisms of cancer-associated DNA polymerase ϵ alleles.
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DOI：
10.1093/nar/gkab160
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发表时间：
2021-04-19
影响因子：
14.9
通讯作者：
Puddu F
中科院分区：
文献类型：
--
作者：
Herzog M;Alonso-Perez E;Salguero I;Warringer J;Adams DJ;Jackson SP;Puddu F
人DNA聚合酶P286 R的核酸外切酶结构域中的单个氨基酸残基变化与结直肠癌的发生相关，并已显示出赋予突变子表型。发现酵母酿酒酵母中相应的Pol β等位基因（pol 2-P301 R）比完全核酸外切酶缺陷的Pol β（pol 2 -4）驱动更大的诱变，这是一种意想不到的超诱变表型。通过研究对突变频率、类型、复制链偏差和序列背景的影响，我们发现，在携带一系列癌症相关Pol？核酸外切酶结构域等位基因的酵母细胞中，通常观察到超诱变。由这些等位基因产生的突变与在pol 2 -4细胞中产生的突变之间的相似性表明产生类似于癌症标签14的突变模式的诱变的共有机制。POL 2超增变子与聚合酶结构域中的突变体pol 2-M644 G的比较降低了Pol的保真度，揭示了序列背景和突变的链偏差中的意想不到的相似性。对核酸外切酶结构域突变细胞特有的突变模式的分析表明，当错配的引物末端不能容纳在校正结构域中时，聚合酶的回溯导致在特定序列背景下观察到的插入和T>A突变。
A single amino acid residue change in the exonuclease domain of human DNA polymerase ϵ, P286R, is associated with the development of colorectal cancers, and has been shown to impart a mutator phenotype. The corresponding Pol ϵ allele in the yeast Saccharomyces cerevisiae (pol2-P301R), was found to drive greater mutagenesis than an entirely exonuclease-deficient Pol ϵ (pol2–4), an unexpected phenotype of ultra-mutagenesis. By studying the impact on mutation frequency, type, replication-strand bias, and sequence context, we show that ultra-mutagenesis is commonly observed in yeast cells carrying a range of cancer-associated Pol ϵ exonuclease domain alleles. Similarities between mutations generated by these alleles and those generated in pol2–4 cells indicate a shared mechanism of mutagenesis that yields a mutation pattern similar to cancer Signature 14. Comparison of POL2 ultra-mutator with pol2-M644G, a mutant in the polymerase domain decreasing Pol ϵ fidelity, revealed unexpected analogies in the sequence context and strand bias of mutations. Analysis of mutational patterns unique to exonuclease domain mutant cells suggests that backtracking of the polymerase, when the mismatched primer end cannot be accommodated in the proofreading domain, results in the observed insertions and T>A mutations in specific sequence contexts.
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影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
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：
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