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. MutL is an important eukaryotic MMR factor. We have examined the contributions of MutL to maintaining genome stability. We show here that loss of MutL 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 MutL 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 MutL 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 MutL-independent MMR plays a role in suppressing base substitutions in N3 homopolymeric runs. In addition, we describe that MutL preferentially defends noncoding DNA from mutations. Our study defines the contributions of MutL-dependent and independent mechanisms to genome-wide MMR.