Guanine holes are prominent targets for mutation in cancer and inherited disease.
Guanine holes are prominent targets for mutation in cancer and inherited disease.
复制标题
DOI：
10.1371/journal.pgen.1003816
复制
发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Vasquez KM
中科院分区：
文献类型：
--
作者：
Bacolla A;Temiz NA;Yi M;Ivanic J;Cer RZ;Donohue DE;Ball EV;Mudunuri US;Wang G;Jain A;Volfovsky N;Luke BT;Stephens RM;Cooper DN;Collins JR;Vasquez KM
单碱基替换是最常见的人类基因突变类型，也是癌症和遗传性疾病的主要原因。这些改变在 DNA 中非随机发生，受到局部核苷酸序列背景的强烈影响。然而，这种序列背景依赖性诱变背后的分子机制尚未完全了解。利用生物信息学、计算和分子建模分析，我们确定了在第二个位置包含突变的所有 64 个 5'-NGNN-3' 基序中 G•C bp 的突变频率。使用了 24 个数据集，包括来自 21 个癌症基因组的 > 530,000 个体细胞单碱基替换、> 77,000 个导致或与人类遗传性疾病相关的种系单碱基替换以及 1,670 万个良性种系单核苷酸变异。在几种癌症类型中，突变基序的数量与碱基堆积的自由能和从目标鸟嘌呤中提取电子所需的能量（电离势）相关。类似的相关性对于病理性错义和无义种系突变也很明显，但仅当目标鸟嘌呤位于非转录 DNA 链上时。同样，致病性剪接突变主要影响非转录 DNA 链上嘌呤的位置。在癌症数据集中还发现了新的候选驱动突变和组织特异性突变模式。我们得出的结论是，DNA 分子内的电子转移反应有助于序列背景依赖性突变，涉及癌症中的体细胞驱动突变和乘客突变，以及导致或与遗传性疾病相关的种系改变。对癌症或人类遗传性疾病患者细胞中发现的大量 DNA 突变进行分析，以解决人类病理学中的一个基本问题，即导致 DNA 不可逆变化的突变机制。通过使用生物信息学和计算方法，我们发现突变不是随机发生的，而是影响特定碱基，最常见的是侧翼有其他鸟嘌呤或腺嘌呤的鸟嘌呤。我们将这种效应归因于电子转移，这是一种化学反应，是细胞呼吸和光合作用等基本生物过程的基础。某些类型的致癌物、氧化剂或辐射可以与 DNA 相互作用并夺取电子。我们的结果表明，随后的电子丢失位点可以从 DNA 中的原始位置迁移到被捕获的邻近鸟嘌呤，导致进一步的化学修饰，最终可能导致突变。许多已知对肿瘤生长很重要的突变（驱动突变）以及过客突变和与遗传性疾病相关的突变似乎是由电子转移引起的。除了病理突变之外，电子转移可能代表了一种普遍机制，通过这种机制，所有生命形式中都会发生遗传变化，从而在进化过程中推动种群适应性。
Single base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G•C bp in the context of all 64 5′-NGNN-3′ motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines (ionization potentials). Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease. A large number of DNA mutations identified in cells from patients with cancer or human inherited disease were analyzed to address a fundamental issue in human pathology, viz, the mutational mechanisms that cause irreversible changes to DNA. By using bioinformatics and computational methods, we found that mutations do not occur randomly, but instead affect specific bases, most often guanines flanked by other guanines or adenines. We attribute this effect to electron transfer, a chemical reaction known to underlie basic biological processes such as cellular respiration and photosynthesis. Certain types of carcinogens, oxidants or radiation can interact with DNA and abstract an electron. Our results imply that the ensuing sites of electron loss can migrate from their original position in the DNA to neighboring guanines where they become trapped, leading to further chemical modifications that may eventually result in mutations. Many of the mutations known to be important for tumor growth (driver mutations), as well as passenger mutations and mutations associated with inherited disease, appear to be caused by electron transfer. Beyond pathological mutations, electron transfer may represent a universal mechanism by which genetic changes occur in all life forms to drive population fitness over evolutionary time.
登录
查看更多内容
影响因子：
3.9
作者：
Cooper, David N.;Bacolla, Albino;Ferec, Claude;Vasquez, Karen M.;Kehrer-Sawatzki, Hildegard;Chen, Jian-Min
通讯作者：
Chen, Jian-Min
影响因子：
3.7
作者：
Derrien T;Estellé J;Marco Sola S;Knowles DG;Raineri E;Guigó R;Ribeca P
通讯作者：
Ribeca P
影响因子：
2
作者：
Fernandez, Alberto;Gomez, Sergio
通讯作者：
Gomez, Sergio
影响因子：
64.8
作者：
Berger, Michael F.;Hodis, Eran;Heffernan, Timothy P.;Deribe, Yonathan Lissanu;Lawrence, Michael S.;Protopopov, Alexei;Ivanova, Elena;Watson, Ian R.;Nickerson, Elizabeth;Ghosh, Papia;Zhang, Hailei;Zeid, Rhamy;Ren, Xiaojia;Cibulskis, Kristian;Sivachenko, Andrey Y.;Wagle, Nikhil;Sucker, Antje;Sougnez, Carrie;Onofrio, Robert;Ambrogio, Lauren;Auclair, Daniel;Fennell, Timothy;Carter, Scott L.;Drier, Yotam;Stojanov, Petar;Singer, Meredith A.;Voet, Douglas;Jing, Rui;Saksena, Gordon;Barretina, Jordi;Ramos, Alex H.;Pugh, Trevor J.;Stransky, Nicolas;Parkin, Melissa;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Wargo, Jennifer;Schadendorf, Dirk;Meyerson, Matthew;Gabriel, Stacey B.;Golub, Todd R.;Wagner, Stephan N.;Lander, Eric S.;Getz, Gad;Chin, Lynda;Garraway, Levi A.
通讯作者：
Garraway, Levi A.
影响因子：
64.8
作者：
Berger, Michael F.;Lawrence, Michael S.;Demichelis, Francesca;Drier, Yotam;Cibulskis, Kristian;Sivachenko, Andrey Y.;Sboner, Andrea;Esgueva, Raquel;Pflueger, Dorothee;Sougnez, Carrie;Onofrio, Robert;Carter, Scott L.;Park, Kyung;Habegger, Lukas;Ambrogio, Lauren;Fennell, Timothy;Parkin, Melissa;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Pugh, Trevor J.;Wilkinson, Jane;Fisher, Sheila;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Simons, Jonathan W.;Kitabayashi, Naoki;MacDonald, Theresa Y.;Kantoff, Philip W.;Chin, Lynda;Gabriel, Stacey B.;Gerstein, Mark B.;Golub, Todd R.;Meyerson, Matthew;Tewari, Ashutosh;Lander, Eric S.;Getz, Gad;Rubin, Mark A.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.