Human DNA mismatch repair: coupling of mismatch recognition to strand-specific excision.
Human DNA mismatch repair: coupling of mismatch recognition to strand-specific excision.
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DOI：
10.1093/nar/gkm734
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发表时间：
2007
影响因子：
14.9
通讯作者：
Hays JB
中科院分区：
文献类型：
--
作者：
Wang H;Hays JB
真核错配修复（MMR）蛋白MutSα和MutLα将碱基错配识别与链特异性切除偶联，在体内从生长的3′末端和5′ Okazaki片段末端或在人核提取物中从外源环状底物的切口开始。我们讨论了五个与耦合模型相关的生物化学问题。在各种错配切口距离下，DNA：MutSα比率接近1：1时，切除仍然完全有效，表明每个底物仅需要一个MutSα分子。当外源底物中的错配-切口DNA轮廓距离D从0.26 kbp增加到0.98 kbp时，提取物中的切除起始降低为D−0.43，而不是某些易位或扩散模型预测的D−1到D−2。几乎所有的切除都是沿着较短的（3′-5′）切口错配，即使另一条（5′-3′）路径的长度不到其两倍。这些观察反对随机定向易位/扩散识别复合物。错配的DNA在反式挑起切除单独的切口homoduplexes反对一个阶段（协同）触发切除起始的识别复合物通过空间作用的失败。然而，与缺口DNA相关的蛋白质似乎与顺式的蛋白质竞争错配相关的蛋白质。因此，在大肠杆菌中，真核MMR可能涉及不同的初始激活和切除路径提交阶段。
Eukaryotic mismatch-repair (MMR) proteins MutSα and MutLα couple recognition of base mismatches to strand-specific excision, initiated in vivo at growing 3′ ends and 5′ Okazaki-fragment ends or, in human nuclear extracts, at nicks in exogenous circular substrates. We addressed five biochemical questions relevant to coupling models. Excision remained fully efficient at DNA:MutSα ratios of nearly 1 to 1 at various mismatch-nick distances, suggesting a requirement for only one MutSα molecule per substrate. As the mismatch-nick DNA contour distance D in exogenous substrates increased from 0.26 to 0.98 kbp, initiation of excision in extracts decreased as D−0.43 rather than the D−1 to D−2 predicted by some translocation or diffusion models. Virtually all excision was along the shorter (3′–5′) nick-mismatch, even when the other (5′–3′) path was less than twice as long. These observations argue against stochastically directed translocating/diffusing recognition complexes. The failure of mismatched DNA in trans to provoke excision of separate nicked homoduplexes argues against one-stage (concerted) triggering of excision initiation by recognition complexes acting through space. However, proteins associated with gapped DNA did appear to compete in trans with those in cis to mismatch-associated proteins. Thus, as in Escherichia coli, eukaryotic MMR may involve distinct initial-activation and excision-path-commitment stages.
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影响因子：
4.8
作者：
Schofield, MJ;Brownewell, FE;Hsieh, P
通讯作者：
Hsieh, P
影响因子：
16
作者：
Junop, MS;Obmolova, G;Yang, W
通讯作者：
Yang, W
DOI：
10.1073/pnas.0705129104
发表时间：
2007-07-31
影响因子：
11.1
作者：
Pluciennik, Anna;Modrich, Paul
通讯作者：
Modrich, Paul
影响因子：
4.8
作者：
Genschel, J;Bazemore, LR;Modrich, P
通讯作者：
Modrich, P
影响因子：
3.8
作者：
Hays, JB;Hoffman, PD;Wang, HX
通讯作者：
Wang, HX