Tumor suppressor function of mismatch repair (MMR) proteins - MMR proteins have a dual role as tumor suppressors. Their repair function ensures genome stability; MMR-dependent DNA damage response eliminates damaged cells by inducing cell death. Defects in either function result in increased genome instability and evasion of cell death, two hallmarks of cancer. Hence, MMR defects contribute significantly to carcinogenesis, failure of chemotherapy and secondary tumor growth. For an advancement in tumor therapy, an understanding of the tumor suppressor function of MMR proteins is mandatory. MMR proteins in DNA damage response. The MMR pathway has been investigated extensively over the past decades. In contrast, though the existence of a MMR-dependent damage response is widely accepted, its mechanistic aspects are largely unknown. The signaling cascade induced in MMR-dependent damage response needs to be investigated. MMR proteins at the interface between cell death and survival. As DNA damage sensors, MutS homologous proteins are excellent candidates for the identification of the nature and extent of damage, its processing and the induction of appropriate responses. The induction of pathways resulting in either cell death or survival requires tight regulation and coordination. The nature of the initial signal, and the mechanism and extent to which MMR proteins function in the coordination of different pathways is currently unknown. A systematic investigation of MMR-dependent damage response. - Genetic studies on alterations in overall cell survival and specific apoptotic signaling in DNA damage response (Aim1) will be complemented with biochemical studies of functional defects associated with mutant proteins (Aim2) and compared to requirements in repair. Downstream proteins involved in the MMR-dependent cell death signaling cascade will be analyzed in dependence of MMR protein function and the DNA damage signal (Aim3). Expected Outcome: This research will provide first insights into the tumor suppressor role of MMR proteins at the decision point between cell death and survival, and identify the molecular mechanism of MMR-dependent damage response. An understanding of this mechanism will funnel into the long term goal of this project that is aimed at the improvement of diagnosis and treatment of cancer patients tailored towards the individual's needs.
|Gassman, Natalie R; Clodfelter, Jill E; McCauley, Anita K et al. (2011) Cooperative nuclear localization sequences lend a novel role to the N-terminal region of MSH6. PLoS One 6:e17907|
|Norris, Alixanna M; Gentry, Michael; Peehl, Donna M et al. (2009) The elevated expression of a mismatch repair protein is a predictor for biochemical recurrence after radical prostatectomy. Cancer Epidemiol Biomarkers Prev 18:57-64|
|Topping, Ryan P; Wilkinson, John C; Scarpinato, Karin Drotschmann (2009) Mismatch repair protein deficiency compromises cisplatin-induced apoptotic signaling. J Biol Chem 284:14029-39|
|Vasilyeva, Aksana; Clodfelter, Jill E; Rector, Brian et al. (2009) Small molecule induction of MSH2-dependent cell death suggests a vital role of mismatch repair proteins in cell death. DNA Repair (Amst) 8:103-13|
|Salsbury Jr, Freddie R; Clodfelter, Jill E; Gentry, Michael B et al. (2006) The molecular mechanism of DNA damage recognition by MutS homologs and its consequences for cell death response. Nucleic Acids Res 34:2173-85|
|Clodfelter, Jill E; B Gentry, Michael; Drotschmann, Karin (2005) MSH2 missense mutations alter cisplatin cytotoxicity and promote cisplatin-induced genome instability. Nucleic Acids Res 33:3323-30|