The cell cycle and DNA mismatch repair
The cell cycle and DNA mismatch repair
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DOI：
10.1016/j.yexcr.2006.10.018
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发表时间：
2007-01-15
影响因子：
3.7
通讯作者：
Williams, Kandace J.
中科院分区：
文献类型：
--
作者：
Schroering, Allen G.;Edelbrock, Michael A.;Williams, Kandace J.
DNA错配修复(MMR)途径通过纠正错配核苷酸和插入/缺失环(IDL)来促进DNA合成和重组的保真度。我们研究了哺乳动物细胞中MMR蛋白的表达、活性和亚细胞位置在细胞周期的不同阶段是否发生了变化。已经使用两种不同的方法证明，尽管在S期，细胞核内生理性的MMR蛋白表达、错配结合和缺口定向的MMR活性处于最高水平，但MMR在整个细胞周期中都是活跃的。尽管MMR核蛋白在S和G(2)期的浓度相等，但G(2)期的错配结合和修复活性显著低于G(2)期，表明翻译后G(2)特异的MMR活性下降。我们进一步证明，2MU的M，N-甲基-N‘-硝基-N-亚硝胺(MNNG)可以破坏典型的MutSα到S晚期复制点的共定位。这种浓度的MNNG不会减少正在进行的DNA合成，也不会诱导细胞周期停滞，直到第二个细胞周期，长期集落存活率仅下降24%。这些结果表明，低水平的烷基化损伤可以选择性地干扰DNA合成过程中MMR的校对活性，并可能增加存活细胞内的突变频率。(C)2006 Elsevier Inc.保留所有权利。
The DNA mismatch repair (MMR) pathway contributes to the fidelity of DNA synthesis and recombination by correcting mispaired nucleotides and insertion/deletion loops (IDLs). We have investigated whether MMR protein expression, activity, and subcellular location are altered during discrete phases of the cell cycle in mammalian cells. Two distinct methods have been used to demonstrate that although physiological MMR protein expression, mismatch binding, and nick-directed MMR activity within the nucleus are at highest levels during S phase, MMR is active throughout the cell cycle. Despite equal MMR nuclear protein concentrations in S and G(2) phases, mismatch binding and repair activities within G(2) are significantly lower, indicating a post-translational decrease in MMR activity specific to G(2). We further demonstrate that typical co-localization of MutS alpha to late S phase replication foci can be disrupted by 2 mu M N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). This concentration of MNNG does not decrease ongoing DNA synthesis nor induce cell cycle arrest until the second cell cycle, with long-term colony survival decreased by only 24%. These results suggest that low level alkylation damage can selectively disrupt MMR proofreading activity during DNA synthesis and potentially increase mutation frequency within surviving cells. (c) 2006 Elsevier Inc. All rights reserved.