Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications.
Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications.
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不同的不匹配修复缺陷都对体细胞过度的影响都具有相同的影响：完整的主要机制伴随着次级修饰。
DOI：
10.1084/jem.190.1.21
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发表时间：
1999-07-05
期刊：
影响因子：
--
通讯作者：
Storb U
中科院分区：
文献类型：
--
作者：
Kim N;Bozek G;Lo JC;Storb U
IG基因的体细胞超突变可能依赖于靶基因通过与RNA聚合酶相关的增变因子的转录（Storb，U.，E.L. Klotz，J. Hackett，Jr.，K. Kage，G. Bozek和T.E.马丁1998. J. Exp. 188：689-698）。也可能是某种形式的DNA修复参与了突变过程。结果表明，不需要核苷酸切除修复蛋白，也不是错配修复（MMR）蛋白。然而，在Msh 2（MutS同源物）和Pms 2（MutL同源物）MMR缺陷小鼠中观察到突变模式和点突变频率的某些变化（综述参见Kim，N.，和联合斯托布1998. J. Exp. 187：1729-1733）。这些数据是从内源性免疫球蛋白（IG）基因中获得的，并可能受到IG基因发生某些突变的B细胞选择的影响。在这项研究中，我们分析了两种MutL类型的MMR缺陷，Pms 2和Mlh 1的体细胞超突变。突变靶点是在V区插入人工插入物的非选择性IG-κ基因。我们发现，Pms 2和Mlh 1缺陷小鼠可以体细胞超突变的IG测试基因在大约两倍减少的频率。此外，高度突变的序列几乎不存在。与在生发中心B细胞中发现的基因组不稳定性一起，这些观察结果支持先前针对Msh 2小鼠得出的结论，即经历体细胞超突变的MMR缺陷型B细胞具有短寿命。Pms 2-和Mlh 1-缺陷型小鼠在优先靶向G和C核苷酸方面也类似于Msh 2-缺陷型小鼠。因此，似乎不同的MMR蛋白在体细胞超突变方面不具有独特的功能。在MMR缺陷小鼠中，体细胞高突变的几个内在特征保持不变：在不可选择的IG基因中，靶向A而非T的偏好、a链偏倚、突变热点和人工插入物的高突变性都被观察到。这意味着MMR蛋白不需要并且很可能不参与引入突变的主要步骤。相反，它们被招募来修复某些体细胞点突变，大概是在这些点突变产生后不久。
Somatic hypermutation of Ig genes is probably dependent on transcription of the target gene via a mutator factor associated with the RNA polymerase (Storb, U., E.L. Klotz, J. Hackett, Jr., K. Kage, G. Bozek, and T.E. Martin. 1998. J. Exp. Med. 188:689–698). It is also probable that some form of DNA repair is involved in the mutation process. It was shown that the nucleotide excision repair proteins were not required, nor were mismatch repair (MMR) proteins. However, certain changes in mutation patterns and frequency of point mutations were observed in Msh2 (MutS homologue) and Pms2 (MutL homologue) MMR-deficient mice (for review see Kim, N., and U. Storb. 1998. J. Exp. Med. 187:1729–1733). These data were obtained from endogenous immunoglobulin (Ig) genes and were presumably influenced by selection of B cells whose Ig genes had undergone certain mutations. In this study, we have analyzed somatic hypermutation in two MutL types of MMR deficiencies, Pms2 and Mlh1. The mutation target was a nonselectable Ig-κ gene with an artificial insert in the V region. We found that both Pms2- and Mlh1-deficient mice can somatically hypermutate the Ig test gene at approximately twofold reduced frequencies. Furthermore, highly mutated sequences are almost absent. Together with the finding of genome instability in the germinal center B cells, these observations support the conclusion, previously reached for Msh2 mice, that MMR-deficient B cells undergoing somatic hypermutation have a short life span. Pms2- and Mlh1-deficient mice also resemble Msh2-deficient mice with respect to preferential targeting of G and C nucleotides. Thus, it appears that the different MMR proteins do not have unique functions with respect to somatic hypermutation. Several intrinsic characteristics of somatic hypermutation remain unaltered in the MMR-deficient mice: a preference for targeting A over T, a strand bias, mutational hot spots, and hypermutability of the artificial insert are all seen in the unselectable Ig gene. This implies that the MMR proteins are not required for and most likely are not involved in the primary step of introducing the mutations. Instead, they are recruited to repair certain somatic point mutations, presumably soon after these are created.
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DOI：
10.1084/jem.187.11.1745
发表时间：
1998-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Phung QH;Winter DB;Cranston A;Tarone RE;Bohr VA;Fishel R;Gearhart PJ
通讯作者：
Gearhart PJ
DOI：
10.1084/jem.187.11.1735
发表时间：
1998-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jacobs H;Fukita Y;van der Horst GT;de Boer J;Weeda G;Essers J;de Wind N;Engelward BP;Samson L;Verbeek S;de Murcia JM;de Murcia G;te Riele H;Rajewsky K
通讯作者：
Rajewsky K
DOI：
10.1073/pnas.86.8.2766
发表时间：
1989-04-01
影响因子：
11.1
作者：
ORITA, M;IWAHANA, H;SEKIYA, T
通讯作者：
SEKIYA, T
影响因子：
64.5
作者：
BETZ, AG;MILSTEIN, C;NEUBERGER, MS
通讯作者：
NEUBERGER, MS
影响因子：
64.5
作者：
BAKER, SM;BRONNER, CE;LISKAY, RM
通讯作者：
LISKAY, RM