Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting
Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting
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DOI：
10.1016/s1074-7613(00)80595-6
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发表时间：
1998-07-01
期刊：
影响因子：
32.4
通讯作者：
Milstein, C
中科院分区：
文献类型：
--
作者：
Rada, C;Ehrenstein, MR;Milstein, C
在体细胞超突变过程中可能会产生错配，这激发了人们对错配修复缺陷对这一过程的影响的兴趣。对生发中心B细胞VH重排3‘位非选择性突变的分析表明，MSH2缺乏导致B倍的突变积累减少。这可能反映了Msh2基因中断的异位效应；事实上，小鼠在B细胞室内表现出其他干扰。然而，MSH2(或依赖于MSH2的因子)在突变固定机制中的作用是通过突变对内在热点的显著增加来表明的。我们提出了两个阶段的超突变靶向。第一个阶段是热点聚焦和MSH2独立阶段；第二个阶段是MSH2依赖阶段，产生更均匀的突变固定。
Likely creation of mismatches during somatic hypermutation has stimulated interest in the effect of mismatch repair deficiency on the process. Analysis of unselected mutations in the 3' Rank of VH rearrangements in germinal center B cells revealed that MSH2 deficiency caused a B-fold reduced mutation accumulation. This might reflect ectopic effects of the Msh2 disruption; indeed, the mice exhibit other perturbations within the B cell compartment. However, that MSH2 (or factors dependent upon it) plays a role in the mechanism of mutation fixation is indicated by a strikingly increased focusing of the mutations on intrinsic hot spots. We propose two phases to hypermutation targeting. The first is hot spot focused and MSH2 independent; the second, MSH2-dependent phase yields a more even spread of mutation fixation.