We develop mechanistic models to understand the critical process of DNA mismatch repair. DNA mismatch repair is a crucial cellular process which corrects errors introduced into the genome during DNA replication, guarding against mutations and disease. In humans, defects in mismatch repair proteins have been linked to a hereditary form of colorectal cancer.
DNA mismatch repair requires a precise communication among repair proteins and the nucleic acid substrate in order to coordinate biochemical steps for DNA repair. Students in my lab use a combination of approaches including protein-nucleic acid photo-crosslinking, reconstituted biochemical reactions, structural biochemistry, and genetic assays to understand the essential signaling steps among repair proteins that are necessary to correct DNA mismatches.
Carol M. Manhart, Xiaodan Ni, Martin A. White, Joaquin Ortega, Jennifer Surtees, and Eric Alani. The mismatch repair and meiotic recombination endonuclease Mlh1-Mlh3 is activated by polymer formation and can cleave DNA substrates in trans, PLoS Biology, 2017, 15 (4): e2001164.
Carol M. Manhart and Eric Alani. Roles for mismatch repair family proteins in promoting meiotic crossing over, DNA Repair (Special Issue), invited review article, 2016, 38: 84-93.
Carol M. Manhart and Charles S. McHenry. Identification of subunit binding positions on a model fork and displacements that occur during sequential assembly of the Escherichia coli primosome, Journal of Biological Chemistry, 2015, 290 (17): 10828-10839.
Maria V. Rogacheva*, Carol M. Manhart*, Cheng Chen, Alba Guarné, Jennifer Surtees, and Eric Alani. Mlh1-Mlh3, a meiotic crossover and DNA mismatch repair factor, is a Msh2-Msh3-stimulated endonuclease, Journal of Biological Chemistry, 2014, 289 (9): 5664-5673. [*contributed equally to this work]
Paul R. Dohrmann, Carol M. Manhart, Christopher D. Downey, and Charles S. McHenry. The rate of polymerase release upon filling the gap between Okazaki fragments is inadequate to support cycling during lagging strand synthesis, Journal of Molecular Biology, 2011, 414 (1): 15-27.