Lynch syndrome-associated mutations in MSH2 alter DNA repair and checkpoint response functions in vivo.
Lynch syndrome-associated mutations in MSH2 alter DNA repair and checkpoint response functions in vivo.
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DOI：
10.1002/humu.21333
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发表时间：
2010-10
期刊：
影响因子：
3.9
通讯作者：
Heinen, Christopher D.
中科院分区：
文献类型：
--
作者：
Mastrocola, Adam S.;Heinen, Christopher D.
DNA错配修复（MMR）途径通过其在DNA修复和检查点应答中的作用在维持基因组稳定性中是必不可少的。DNA MMR的丢失是遗传性癌症疾病Lynch综合征（LS）的基础。MSH 2的生殖系突变约占LS患者的40%，其中18%为错义突变。一个重要的临床挑战是区分致病性和非致病性的错义变体。目前MSH 2错义突变的分析是结合临床、生物化学和功能数据进行的;然而，缺乏合适的细胞培养模型来测试DNA MMR蛋白的各种功能。在这里，我们已经产生了稳定表达MSH 2错义突变体的一个子集的人细胞系，并测试了它们对DNA修复和检查点响应功能的影响。我们已经扩展了以前在非人类系统中进行的生化和功能分析，以进一步了解由该单个氨基酸改变子集所赋予的缺陷。MSH 2错义突变体的功能表征结合临床和生化数据对于适当的患者管理和遗传咨询决策至关重要。©2010 Wiley-Liss公司。
The DNA mismatch repair (MMR) pathway is essential in maintaining genomic stability through its role in DNA repair and the checkpoint response. Loss of DNA MMR underlies the hereditary cancer disease Lynch Syndrome (LS). Germline mutations in MSH2 account for approximately 40% of LS patients and of these, 18% are missense variants. One important clinical challenge has been discriminating between missense variants that are pathogenic and those that are not. Current analysis of missense mutations in MSH2 is performed using a combination of clinical, biochemical, and functional data; however, suitable cell culture models to test the various functions of the DNA MMR proteins are lacking. Here, we have generated human cell lines stably expressing a subset of MSH2 missense mutants and tested their effect on DNA repair and checkpoint response functions. We have expanded on previous biochemical and functional analyses performed in non-human systems to further understand defects conferred by this subset of single amino acid alterations. The functional characterization of MSH2 missense mutants combined with clinical and biochemical data is essential for appropriate patient management and genetic counseling decisions. ©2010 Wiley-Liss, Inc.
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