Unravelling roles of error-prone DNA polymerases in shaping cancer genomes.
Unravelling roles of error-prone DNA polymerases in shaping cancer genomes.
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DOI：
10.1038/s41388-021-02032-9
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发表时间：
2021-12
期刊：
影响因子：
8
通讯作者：
Day TA
中科院分区：
文献类型：
--
作者：
Vaziri C;Rogozin IB;Gu Q;Wu D;Day TA
突变是癌细胞的一个关键标志和使能特征，然而形成癌症基因组的多种潜在突变机制尚不清楚。这篇综述将考虑确定DNA损伤反应途径（包括耐受性和修复）如何作用于特定形式的DNA损伤以产生肿瘤特征突变的新挑战。DNA聚合酶通常是DNA修复途径的最终诱变效应物。因此，了解DNA聚合酶的作用对于更全面地了解肿瘤致突变机制至关重要。为特定的DNA模板选择合适的DNA聚合酶，无论是无错误的还是容易出错的，对于维持基因组的稳定性至关重要。我们回顾了DNA聚合酶失调的不同模式，包括突变、多态性和聚合酶本身或其相关激活物的过表达。基于最近发现的DNA聚合酶与特定的突变机制之间的联系，我们提出易出错的聚合酶对DNA修复缺陷的补偿可能是塑造癌细胞突变景观的一般范例。值得注意的是，我们证明了来自癌症基因组图谱的一部分患者肿瘤中易出错聚合酶表达与突变负担的相关性，可以为进一步的测试确定机制假设。我们对比了实验方法从广泛的，全基因组战略的方法与狭窄的重点在几百个碱基对的DNA。此外，我们考虑了最近在患者肿瘤数据的计算注释的发展，以确定突变的模式。最后，我们讨论了创新和未来的实验，将发展更全面的人类肿瘤致突变机制的画像。
Mutagenesis is a key hallmark and enabling characteristic of cancer cells, yet the diverse underlying mutagenic mechanisms that shape cancer genomes are not understood. This review will consider the emerging challenge of determining how DNA damage response pathways—both tolerance and repair—act upon specific forms of DNA damage to generate mutations characteristic of tumors. DNA polymerases are typically the ultimate mutagenic effectors of DNA repair pathways. Therefore, understanding the contributions of DNA polymerases is critical to develop a more comprehensive picture of mutagenic mechanisms in tumors. Selection of an appropriate DNA polymerase—whether error-free or error-prone—for a particular DNA template is critical to the maintenance of genome stability. We review different modes of DNA polymerase dysregulation including mutation, polymorphism, and over-expression of the polymerases themselves or their associated activators. Based upon recent findings connecting DNA polymerases with specific mechanisms of mutagenesis, we propose that compensation for DNA repair defects by error-prone polymerases may be a general paradigm molding the mutational landscape of cancer cells. Notably, we demonstrate that correlation of error-prone polymerase expression with mutation burden in a subset of patient tumors from The Cancer Genome Atlas can identify mechanistic hypotheses for further testing. We contrast experimental approaches from broad, genome-wide strategies to approaches with a narrower focus on a few hundred base pairs of DNA. In addition, we consider recent developments in computational annotation of patient tumor data to identify patterns of mutagenesis. Finally, we discuss the innovations and future experiments that will develop a more comprehensive portrait of mutagenic mechanisms in human tumors.
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影响因子：
4
作者：
Alexandrov, Ludmil B.;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
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
影响因子：
14.9
作者：
Arana, Mercedes E.;Seki, Mineaki;Wood, Richard D.;Rogozin, Igor B.;Kunkel, Thomas A.
通讯作者：
Kunkel, Thomas A.
影响因子：
30.8
作者：
Chan K;Roberts SA;Klimczak LJ;Sterling JF;Saini N;Malc EP;Kim J;Kwiatkowski DJ;Fargo DC;Mieczkowski PA;Getz G;Gordenin DA
通讯作者：
Gordenin DA
DOI：
10.1073/pnas.1603388113
发表时间：
2016-04-12
影响因子：
11.1
作者：
Adar, Sheera;Hu, Jinchuan;Sancar, Aziz
通讯作者：
Sancar, Aziz