DNA mismatch repair is a key mutation avoidance pathway that is of clinical interest for several reasons. Inactivation of mismatch repair is the cause of a common form of hereditary colon cancer and has been implicated in the development of a subset of sporadic tumors. Mismatch repair defects also have implications for cancer therapy because inactivation of the pathway renders cells resistant to the cytotoxic effects of certain anti-tumor drugs, a consequence of participation of the system in the DNA damage response. Perhaps surprisingly, mismatch repair function is also required for the production of certain mutations, such as the expansion of (CAG)n repeat sequences, the primary cause of a number of neurodegenerative diseases. By elucidating the molecular nature of human mismatch repair, we hope to understand its roles in controlling the occurrence of mutation. To this end we propose four lines of work: (1) Available information on the nature of strand-directed human mismatch repair indicates that the course of the reaction is dictated by an evolving set of protein-protein and protein-DNA interactions, and that repair events initiated by the mismatch recognition activities MutS1 and MutS2 differ in significant ways. By analyzing the nature of selected multi-protein and multi-protein-DNA complexes, we hope to further clarify the mechanisms of MutS1- and MutS2-initiated repair events. (2) The somatic expansion stage of (CAG)n neurodegenerative diseases, which depends on the mismatch repair activities MutS2 and MutL1, can occur in postmitotic cells, suggesting involvement of repair DNA synthesis in this process. The nature of processing of (CAG)n repeat elements by the human mismatch repair system will be addressed in both extract and purified systems. (3) Mismatch repair function is required for checkpoint and apoptotic responses to SN1 DNA methylators. Using a biochemical approach, we will pursue the mechanisms of MutS1- and MutL1-dependent activation of the ATR damage-signaling kinase in response to O6-methylguanine, the primary cytotoxic lesion produced by this class of drug. (4) Collaborative studies with the laboratory of Lorena Beese will address the structural basis of lesion recognition and processing by the human mismatch recognition system.
DNA mismatch repair provides multiple mutation avoidance functions, and its inactivation is the cause of a common form of hereditary colon cancer. Surprisingly, pathway function is also required for the production of certain mutations, such as the expansion of (CAG)n repeat sequences, the primary cause of a number of neurodegenerative diseases. By clarifying the molecular nature of mismatch repair, we hope to understand its functions in the control of mutation production.
|Sherrer, Shanen M; Penland, Elisabeth; Modrich, Paul (2018) The mutagen and carcinogen cadmium is a high-affinity inhibitor of the zinc-dependent MutL? endonuclease. Proc Natl Acad Sci U S A 115:7314-7319|
|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|
|Chen, Yu-Tsung Shane; Wu, Jianhong; Modrich, Paul et al. (2016) The C-terminal 20 Amino Acids of Drosophila Topoisomerase 2 Are Required for Binding to a BRCA1 C Terminus (BRCT) Domain-containing Protein, Mus101, and Fidelity of DNA Segregation. J Biol Chem 291:13216-28|
|Modrich, Paul (2016) Mechanisms in E. coli and Human Mismatch Repair (Nobel Lecture). Angew Chem Int Ed Engl 55:8490-501|
|Qiu, Ruoyi; Sakato, Miho; Sacho, Elizabeth J et al. (2015) MutL traps MutS at a DNA mismatch. Proc Natl Acad Sci U S A 112:10914-9|
|Lindsey-Boltz, Laura A; Kemp, Michael G; Reardon, Joyce T et al. (2014) Coupling of human DNA excision repair and the DNA damage checkpoint in a defined in vitro system. J Biol Chem 289:5074-82|
|Shao, Hongbing; Baitinger, Celia; Soderblom, Erik J et al. (2014) Hydrolytic function of Exo1 in mammalian mismatch repair. Nucleic Acids Res 42:7104-12|
|Pluciennik, Anna; Burdett, Vickers; Baitinger, Celia et al. (2013) Extrahelical (CAG)/(CTG) triplet repeat elements support proliferating cell nuclear antigen loading and MutL? endonuclease activation. Proc Natl Acad Sci U S A 110:12277-82|
|Tseng, Quincy; Orans, Jillian; Hast, Michael A et al. (2011) Purification, crystallization and preliminary X-ray diffraction analysis of the human mismatch repair protein MutS?. Acta Crystallogr Sect F Struct Biol Cryst Commun 67:947-52|
|Liu, Yiyong; Kadyrov, Farid A; Modrich, Paul (2011) PARP-1 enhances the mismatch-dependence of 5'-directed excision in human mismatch repair in vitro. DNA Repair (Amst) 10:1145-53|
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