Research in our laboratory addresses the nature of
DNA mismatch repair, a mutation avoidance system with
multiple genetic stabilization functions. We have
reconstituted E. coli mismatch repair in a pure system
comprised of eleven activities, including the MutH,
MutL, MutS, and MutU proteins. Current work on the
bacterial pathway addresses the mechanism of this
complex reaction. We have also identified several
activities required for mismatch repair in human cells,
including MutSalpha, MutSbeta, MutLalpha, EXOI, RPA,
and DNA polymerase delta. Genetic inactivation MutSalpha
or MutLalpha is the cause of hereditary nonpolyposis
colon cancer, and has been implicated in the development
of a subset of sporadic tumors that occur in a variety
of tissues. We have shown that MutSa or MutLa are
involved in the correction of DNA biosynthetic errors,
are required for the apoptotic response to several
DNA-damaging anti-cancer drugs, and prevent the occurrence
of gene duplications. The molecular nature of the
human repair system and its role in these processes
are currently under study in the lab.
