Oxidative stress-induced mutagenesis in single-strand DNA occurs primarily at cytosines and is DNA polymerase zeta-dependent only for adenines and guanines.
Oxidative stress-induced mutagenesis in single-strand DNA occurs primarily at cytosines and is DNA polymerase zeta-dependent only for adenines and guanines.
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DOI：
10.1093/nar/gkt671
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发表时间：
2013-10
影响因子：
14.9
通讯作者：
Doetsch PW
中科院分区：
文献类型：
--
作者：
Degtyareva NP;Heyburn L;Sterling J;Resnick MA;Gordenin DA;Doetsch PW
最近在几种类型的癌症中发现了由持久性单链（ss）DNA中的损伤累积引起的局部超突变性。内源性活性氧（ROS）水平的增加被认为是癌症的标志之一。采用酵母模型系统，我们解决了氧化应激的作用作为一个潜在的来源，超突变的ssDNA的内源性ROS水平的调制和暴露细胞的氧化DNA损伤剂。我们在这里报告，在氧化应激条件下，大多数的碱基置换突变的ssDNA是由错误的，DNA聚合酶（Pol）zeta-独立的胞嘧啶旁路，导致C到T的转换。对于所有其他DNA碱基，Pol zeta对于ROS诱导的诱变是必需的。与UV和MMS引起的突变相比，ROS诱导的ssDNA突变密度较低，这表明ssDNA可以被主动保护免受氧化损伤。这些发现对于理解氧化诱变的机制具有重要意义，并可应用于抗癌疗法和癌症预防的开发。
Localized hyper-mutability caused by accumulation of lesions in persistent single-stranded (ss) DNA has been recently found in several types of cancers. An increase in endogenous levels of reactive oxygen species (ROS) is considered to be one of the hallmarks of cancers. Employing a yeast model system, we addressed the role of oxidative stress as a potential source of hyper-mutability in ssDNA by modulation of the endogenous ROS levels and by exposing cells to oxidative DNA-damaging agents. We report here that under oxidative stress conditions the majority of base substitution mutations in ssDNA are caused by erroneous, DNA polymerase (Pol) zeta-independent bypass of cytosines, resulting in C to T transitions. For all other DNA bases Pol zeta is essential for ROS-induced mutagenesis. The density of ROS-induced mutations in ssDNA is lower, compared to that caused by UV and MMS, which suggests that ssDNA could be actively protected from oxidative damage. These findings have important implications for understanding mechanisms of oxidative mutagenesis, and could be applied to development of anticancer therapies and cancer prevention.
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影响因子：
5.3
作者：
Degtyareva, Natalya P.;Chen, Lingling;Doetsch, Paul W.
通讯作者：
Doetsch, Paul W.
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
DOI：
10.1016/j.bbapap.2012.10.005
发表时间：
2013-01
影响因子：
3.2
作者：
Brooks, Sonja C.;Adhikary, Suraj;Rubinson, Emily H.;Eichman, Brandt F.
通讯作者：
Eichman, Brandt F.
DOI：
10.1073/pnas.1004432107
发表时间：
2010-08-24
影响因子：
11.1
作者：
Mesquita, Ana;Weinberger, Martin;Ludovico, Paula
通讯作者：
Ludovico, Paula
DOI：
10.1073/pnas.88.21.9473
发表时间：
1991-11-01
影响因子：
11.1
作者：
MORRISON, A;BELL, JB;SUGINO, A
通讯作者：
SUGINO, A