Investigating the Role of the MutLα Endonuclease Public Deposited

http://ir.library.oregonstate.edu/concern/undergraduate_thesis_or_projects/df65vd215

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  • Lynch individuals have a predisposition to developing colorectal and other cancers due to inherited defects in their mismatch repair (MMR) system. Although mutations in MMR have been directly implicated in Lynch Syndrome, the precise mechanism(s) of MMR functions have yet to be elucidated. One essential complex, MutL (a dimer of PMS2 and MLH1), contributes to the correction of base insertion and deletion loops, single-base mismatches, and is necessary to trigger apoptosis in response to several types of DNA damage. A recent study by Kaydrov and colleagues showed that MutLα has an endonucleolytic activity only necessary for providing a loading site for the 5’-3’ directed ExoI in a reconstituted in vitro MMR and that a recombinant MutLa deficient for endonucleolytic activity (PMS2-E705K) was unable to repair a 3’ nicked substrate. In related studies, Deschenes et al. showed that hMutL-E705K was unable to restore MMR activity to cytoplasmic extracts from hMutLα-deficient cells using a 5’-nicked substrate. Based on the contradictory findings by Kadyrov et al. and Deschenes et al., we investigated the ability of MutLa-E705K, in comparison to MutLa-WT, to restore repair activity in a reconstituted MMR system using a 3’, 5’, or a 3’/5’ nicked substrate. We present preliminary data showing that hMutL-WT does and hMutL-E705K does not support a reconstituted in vitro repair system when provided with a 3’, 5’ or 3’/5’-nicked substrate, suggesting additional roles for MutLa endonucleolytic activity in in vitro MMR.
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