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与有丝分裂基因转换相关的突变增加和独特的突变特征。

Increased mutagenesis and unique mutation signature associated with mitotic gene conversion.

机构信息

Department of Biology and Rosenstiel Center, Brandeis University, Waltham, MA 02454-9110, USA.

出版信息

Science. 2010 Jul 2;329(5987):82-5. doi: 10.1126/science.1191125.


DOI:10.1126/science.1191125
PMID:20595613
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4254764/
Abstract

To examine the fidelity of DNA synthesis during double-strand break (DSB) repair in Saccharomyces cerevisiae we studied gene conversion in which both strands of DNA are newly synthesized. The mutation rate increases up to 1400 times over spontaneous events, with a significantly different mutation signature. Especially prominent are microhomology-mediated template switches. Recombination-induced mutations are largely independent of mismatch repair, by DNA polymerases Polzeta, Poleta, and Pol32, but result from errors made by Poldelta and Polepsilon. These observations suggest that increased DSB frequencies in oncogene-activated mammalian cells may also increase the probability of acquiring mutations required for transition to a cancerous state.

摘要

为了研究双链断裂(DSB)修复过程中 DNA 合成的忠实性,我们研究了双链 DNA 均被新合成的基因转换。在这个过程中,突变率比自发事件增加了 1400 倍,并且具有明显不同的突变特征。特别突出的是微同源介导的模板转换。由 DNA 聚合酶 Polzeta、Poleta 和 Pol32 引发的重组诱导突变在很大程度上不依赖于错配修复,而是由 Poldelta 和 Polepsilon 造成的错误导致的。这些观察结果表明,癌基因激活的哺乳动物细胞中双链断裂频率的增加也可能增加获得向癌变状态转变所需突变的概率。

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本文引用的文献

[1]
DNA polymerase epsilon and delta proofreading suppress discrete mutator and cancer phenotypes in mice.

Proc Natl Acad Sci U S A. 2009-9-24

[2]
Mechanisms of change in gene copy number.

Nat Rev Genet. 2009-8

[3]
Aberrant double-strand break repair resulting in half crossovers in mutants defective for Rad51 or the DNA polymerase delta complex.

Mol Cell Biol. 2009-3

[4]
Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.

PLoS Genet. 2008-11

[5]
Flexibility of eukaryotic Okazaki fragment maturation through regulated strand displacement synthesis.

J Biol Chem. 2008-12-5

[6]
Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms.

PLoS Genet. 2008-9-5

[7]
Cancers exhibit a mutator phenotype: clinical implications.

Cancer Res. 2008-5-15

[8]
An oncogene-induced DNA damage model for cancer development.

Science. 2008-3-7

[9]
Estimating the per-base-pair mutation rate in the yeast Saccharomyces cerevisiae.

Genetics. 2008-1

[10]
DNA polymerase delta is preferentially recruited during homologous recombination to promote heteroduplex DNA extension.

Mol Cell Biol. 2008-2

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