Career Development Award: Center for Appalachian Research in Environmental Sciences: Mismatch Repair and Environmental DNA Damage

As humans we are exposed to DNA damaging agents in our environment. Left unrepaired this environmental DNA damage can lead to cell death, causing disease due to loss of overall organ function, or it can change the DNA permanently as a mutation, increasing the risk of environmentally induced cancer. One DNA repair pathway that interacts with environmental DNA damage is the DNA mismatch repair pathway. In specific it recognizes DNA damage that results in a wrong pairing between the damaged base and the newly synthesized daughter strand. An example of such is the alkylation induced O6-meG lesion preferentially mispairs with a T instead of the correct base, C. DNA mismatch repair is not designed to adequately repair these damageinduced mispairs, rather its normal function is to act as spell-check shortly after normal replication. In the case of damage-induced mispairs mismatch repair recognizes the mispair, but ultimately signals for cell cycle arrest and apoptotic cell death. Our research program focuses on unraveling the mechanistic steps from mismatch repair recognition of environmental damage through either futile cycling or direct signaling to apoptosis. We have recently identified new physical interacting proteins with a key mismatch repair gene, Msh2. We are determining what role these associated proteins play in alkylation response. Finally, we hope to probe the interplay between heavy metals, mismatch repair and alkylation damage induced cell death. Specific Aims Aim 1. Determine mechanisms of alkylation induced apoptosis using separation of function mutations Aim 2. The role of novel MMR interacting partners in alkylation induced apoptosis Aim 3. The interaction between heavy metals and MMR in response to alkylating agents