GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one.

ABSTRACT: DNA repeat expansion underlies dozens of progressive neurodegenerative disorders. While the mechanisms driving repeat expansion are not fully understood, increasing evidence suggests a central role for DNA mismatch repair. The mismatch repair recognition complex MutSβ (MSH2-MSH3) that binds mismatched bases and/or insertion/deletion loops has previously been implicated in GAA•TTC, CAG•CTG and CGG•CCG repeat expansion, suggesting a shared mechanism. MutSβ has been studied in a number of models, but the contribution of subsequent steps mediated by the MutL endonuclease in this pathway is less clear. Here we show that MutLγ (MLH1-MLH3) is the MutL complex responsible for GAA•TTC repeat expansion. Lentiviral expression of shRNA targeting MutL nuclease components MLH1, PMS2, and MLH3 revealed t

SUBMITTER: Halabi A 

PROVIDER: S-EPMC5934671 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature