MutLα suppresses error-prone DNA mismatch repair and preferentially protects noncoding DNA from mutations

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’-A T A-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’-N T N-3’ sequences. Our further analysis has shown that MutLα-independent MMR plays a role in suppressing base substitutions in N ₃ homopolymeric runs. In addition, we describe that MutLα preferentially defends noncoding DNA from mutations. Our study defines the contributions of MutLα-dependent and independent mechanisms to genome-wide MMR.