Class switch recombination efficiency and junction microhomology patterns in Msh2-, Mlh1-, and Exo1-deficient mice depend on the presence of mu switch region tandem repeats.
Class switch recombination efficiency and junction microhomology patterns in Msh2-, Mlh1-, and Exo1-deficient mice depend on the presence of mu switch region tandem repeats.
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DOI：
10.4049/jimmunol.0900135
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Selsing E
中科院分区：
文献类型：
--
作者：
Eccleston J;Schrader CE;Yuan K;Stavnezer J;Selsing E
Msh 2错配修复（MMR）蛋白对于缺乏Sμ串联重复（SμTR）区域的小鼠（SμTR−/−小鼠）中发生的类别转换重组（CSR）事件至关重要。Msh 2缺陷小鼠开关连接位点之间的微同源性模式也取决于SμTR序列的存在或不存在。目前尚不清楚这些CSR效应是否反映了Msh 2的个体功能或Msh 2在MMR机制中的功能。在缺少SμTR序列的情况下，Msh 2缺陷几乎消除了CSR。我们现在发现，Mlh 1或Exo 1缺陷也会在SμTR缺失的情况下消除CSR。此外，在SμTR−/−小鼠中，Mlh 1或Exo 1的缺陷导致开关连接微同源性增加，如Msh 2缺陷所见。这些结果与CSR模型一致，其中MMR机制在处理DNA切口以产生双链断裂中是重要的，特别是在切口不常见的序列中。我们提出，在MMR缺陷小鼠的双链断裂缺乏导致增加使用的替代连接途径，其中微同源性是重要的CSR断裂连接。有趣的是，当SμTR区域存在时，Msh 2的缺陷不会导致Mlh 1或Exo 1缺陷所见的微同源性增加，这表明Msh 2可能在CSR中具有额外的功能。也有可能在Msh 2缺失的情况下不能启动MMR导致CSR连接的微同源性低于启动MMR时发生的连接，但随后由于Mlh 1或Exo 1缺陷而异常进行。
The Msh2 mismatch repair (MMR) protein is critical for class switch recombination (CSR) events that occur in mice that lack the Sμ tandem repeat (SμTR) region (SμTR−/− mice). The pattern of microhomology among switch junction sites in Msh2-deficient mice is also dependent on the presence or absence of SμTR sequences. It is not known whether these CSR effects reflect an individual function of Msh2 or the function of Msh2 within the MMR machinery. In the absence of the SμTR sequences, Msh2 deficiency nearly ablates CSR. We now show that Mlh1 or Exo1 deficiencies also eliminate CSR in the absence of the SμTR. Furthermore, in SμTR−/− mice, deficiencies of Mlh1 or Exo1 result in increased switch junction microhomology as has also been seen with Msh2 deficiency. These results are consistent with a CSR model in which the MMR machinery is important in processing DNA nicks to produce double-stranded breaks, particularly in sequences where nicks are infrequent. We propose that double-stranded break paucity in MMR-deficient mice leads to increased use of an alternative joining pathway where microhomologies are important for CSR break ligation. Interestingly, when the SμTR region is present, deficiency of Msh2 does not lead to the increased microhomology seen with Mlh1 or Exo1 deficiencies, suggesting that Msh2 might have an additional function in CSR. It is also possible that the inability to initiate MMR in the absence of Msh2 results in CSR junctions with less microhomology than joinings that occur when MMR is initiated but then proceeds abnormally due to Mlh1 or Exo1 deficiencies.
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