Human MutL?, the MLH1-MLH3 heterodimer, is an endonuclease that promotes DNA expansion.

ABSTRACT: MutL proteins are ubiquitous and play important roles in DNA metabolism. MutL? (MLH1-MLH3 heterodimer) is a poorly understood member of the eukaryotic family of MutL proteins that has been implicated in triplet repeat expansion, but its action in this deleterious process has remained unknown. In humans, triplet repeat expansion is the molecular basis for ?40 neurological disorders. In addition to MutL?, triplet repeat expansion involves the mismatch recognition factor MutS? (MSH2-MSH3 heterodimer). We show here that human MutL? is an endonuclease that nicks DNA. Strikingly, incision of covalently closed, relaxed loop-containing DNA by human MutL? is promoted by MutS? and targeted to the strand opposite the loop. The resulting strand break licenses downstream events that lead to a DNA expansion event in human cell extracts. Our data imply that the mammalian MutL? is a unique endonuclease that can initiate triplet repeat DNA expansions.

SUBMITTER: Kadyrova LY 

PROVIDER: S-EPMC7035508 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature