DNA mismatch repair (MMR) maintains genetic stability by correcting mismatches, initiating apoptosis in response to several forms of irreparable DNA damage, and suppressing homologous recombination. Mutational or epigenetic inactivation of MMR causes profound genetic instability and underlies several inherited and sporadic forms of cancer. The therapeutic importance of MMR is highlighted by the fact that tumor cells lacking MMR resist to the cytotoxic effects of several common anticancer drugs. Previous research has been focused on understanding MMR in the context of naked DNA, and little is known about the action of MMR in the nucleosomal environment. Our preliminary data support the overarching hypothesis that there is active interplay and cooperation between the actions of MMR and the nucleosomal environment. The goal of the proposed research is to comprehensively test this hypothesis.
Our first aim i s to investigate the apoptotic function of MMR in the context of the nucleosomal environment.
Our second aim i s to study the impact of the nucleosomal environment on the mismatch correction function of MMR.
Our third aim i s to examine the cooperation between the mismatch correction function of MMR and histone H3-K56 acetylation in promoting genetic stability. To achieve these aims we will take advantage of our unique expertise in performing genetic, biochemical, and molecular biology studies of MMR. The obtained results will significantly contribute to our understanding of the action of human MMR and the potential of using histone chaperone inhibitors for improving the effects of the anticancer drugs.

Public Health Relevance

Defects in DNA mismatch repair (MMR) are the primary basis of hereditary nonpolyposis colorectal cancer (HNPCC) and Turcot syndromes, and a significant fraction of sporadic cancers. Several drugs kill cancer cells via activating the apoptotic function of MMR. This project is designed to advance our understanding of human MMR and to investigate whether the effectiveness of the anticancer drugs can be improved.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Janes, Daniel E
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Southern Illinois University Carbondale
Schools of Medicine
United States
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Genschel, Jochen; Kadyrova, Lyudmila Y; Iyer, Ravi R et al. (2017) Interaction of proliferating cell nuclear antigen with PMS2 is required for MutL? activation and function in mismatch repair. Proc Natl Acad Sci U S A 114:4930-4935
Dahal, Basanta K; Kadyrova, Lyudmila Y; Delfino, Kristin R et al. (2017) Involvement of DNA mismatch repair in the maintenance of heterochromatic DNA stability in Saccharomyces cerevisiae. PLoS Genet 13:e1007074
Kadyrova, Lyudmila Y; Dahal, Basanta K; Kadyrov, Farid A (2016) The Major Replicative Histone Chaperone CAF-1 Suppresses the Activity of the DNA Mismatch Repair System in the Cytotoxic Response to a DNA-methylating Agent. J Biol Chem 291:27298-27312
Rodriges Blanko, Elena; Kadyrova, Lyudmila Y; Kadyrov, Farid A (2016) DNA Mismatch Repair Interacts with CAF-1- and ASF1A-H3-H4-dependent Histone (H3-H4)2 Tetramer Deposition. J Biol Chem 291:9203-17
Kadyrova, Lyudmila Y; Kadyrov, Farid A (2016) Endonuclease activities of MutL? and its homologs in DNA mismatch repair. DNA Repair (Amst) 38:42-9
Kadyrova, Lyudmila Y; Dahal, Basanta K; Kadyrov, Farid A (2015) Evidence that the DNA mismatch repair system removes 1-nucleotide Okazaki fragment flaps. J Biol Chem 290:24051-65
Kadyrova, Lyudmila Y; Mertz, Tony M; Zhang, Yu et al. (2013) A reversible histone H3 acetylation cooperates with mismatch repair and replicative polymerases in maintaining genome stability. PLoS Genet 9:e1003899
Kadyrova, Lyudmila Y; Rodriges Blanko, Elena; Kadyrov, Farid A (2013) Human CAF-1-dependent nucleosome assembly in a defined system. Cell Cycle 12:3286-97