Graduate Student Samuel Pash

There are many natural repair mechanisms within eukaryotic cells that monitor and repair DNA damage and abnormalities. If left untreated, accumulated DNA damage can result in permanent cellular impairment or can lead to tumorigenesis. The process of Mismatch Repair (MMR) is one such repair mechanism, targeting and correcting for mismatched nucleotide base pairs that occur due to mistakes in DNA replication. MMR is initiated by the recognition of a base pair mismatch by an enzyme in the Mutator S (MutS) family, which can then recruit the Mutator L (MutL) enzyme to nick the DNA to start the excision and repair of the mismatched DNA. However, the sequence of events that leads to the successful excision of the mismatched pair is unknown, with the motility of MutS after mismatch recognition being a point of contention for several proposed models of MMR. This seminar will overview several recent publications that have sought to resolve this controversy by investigating the sliding capability of eukaryotic MutSα once bound to a mismatch, and by utilizing atomic force microscopy to visualize MutS-DNA-MutL complex formations to better elucidate the nature of eukaryotic based MMR.

References:
Ortega, J., Lee, G.S., Gu, L. et al. Mispair-bound human MutS–MutL complex triggers DNA incisions and activates mismatch repair. Cell Res 2021, 31, 542–553.

Fernandez-Leiro, R., Bhairosing-Kok, D., Kunetsky, V. et al. The selection process of licensing a DNA mismatch for repair. Nat Struct Mol Biol 2021, 28, 373–381.

Bradford, K., Wilkins, H., Hao, P., Li, Z., et al. Dynamic human MutSα– MutLα complexes compact mismatched DNA Proceedings of the Natural Academy of Sciences 2020, 117(28), 16302-16312.