PDF(Pubmed)
Abstract：
The DNA mismatch repair (MMR) system promotes genome stability and protects humans from certain types of cancer. Its primary function is the correction of DNA polymerase errors. MutLα is an important eukaryotic MMR factor. We have examined the contributions of MutLα to maintaining genome stability. We show here that loss of MutLα in yeast increases the genome-wide mutation rate by ∼130-fold and generates a genome-wide mutation spectrum that consists of small indels and base substitutions. We also show that loss of yeast MutLα leads to error-prone MMR that produces T > C base substitutions in 5\'-ATA-3\' sequences. In agreement with this finding, our examination of human whole-genome DNA sequencing data has revealed that loss of MutLα in induced pluripotent stem cells triggers error-prone MMR that leads to the formation of T > C mutations in 5\'-NTN-3\' sequences. Our further analysis has shown that MutLα-independent MMR plays a role in suppressing base substitutions in N3 homopolymeric runs. In addition, we describe that MutLα preferentially protects noncoding DNA from mutations. Our study defines the contributions of MutLα-dependent and independent mechanisms to genome-wide MMR.
摘要：
DNA错配修复（MMR）系统可促进基因组稳定性并保护人类免受某些类型的癌症侵害。其主要功能是纠正DNA聚合酶错误。MutLα是一种重要的真核MMR因子。我们已经检查了MutLα对维持基因组稳定性的贡献。我们在这里表明，酵母中MutLα的丢失使全基因组突变率增加了约130倍，并产生了由小的插入缺失和碱基取代组成的全基因组突变谱。我们还表明，酵母MutLα的丢失导致易错的MMR，其在5'-ATA-3'序列中产生T>C碱基取代。与这一发现一致，我们对人类全基因组DNA测序数据的检查显示,诱导性多能干细胞中MutLα的缺失会引发易错MMR,导致5\'-NTN-3\'序列中T>C突变的形成.我们的进一步分析表明，不依赖MutLα的MMR在抑制N3同聚序列中的碱基取代中起作用。此外,我们描述了MutLα优先保护非编码DNA免受突变。我们的研究定义了MutLα依赖性和独立机制对全基因组MMR的贡献。
