Determination of P21 downstream signaling in the toxicity of MC and DMC DNA interstrand crosslinks (Student: Kameza Harun)

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Summary: The overarching goal of the parent proposal for this “research supplement to promote diversity in health-related research” is to investigate the relationship between the structure of stereoisomeric DNA Interstrand Crosslinks (ICLs) formed by Mitomycin C and Decarbamoylmitomycin C and the molecular mechanisms of these drugs. Mitomycin C (MC) is an anticancer drug currently used to treat stomach, anal and lung cancers. The stereochemical configuration at C1’’ of MC major ICL is R (α-ICL). In contrast, Decarbamoylmitomycin C (DMC), a derivative of MC lacking the O10 carbamoyl group, generates the S stereoisomeric ICL (β-ICL). The scientific premise of the proposed research is that ICLs constitute the molecular basis for the cytotoxic effects of mitomycins. The central hypothesis is that differences in the local DNA structures of the α and β- ICLs are responsible for the distinct biochemical responses triggered by MC and DMC. In particular, contrary to MC, the DNA-adducts generated by DMC treatment (-ICL) rapidly activate a p53-independent cell death pathway. Thus, the study MC-DMC provides an ideal model for identifying structural features determining the cell signaling outcome in the presence or the absence of a functioning p53 pathway. Since p53 tumor suppressor is frequently mutated in human cancers, the need to identify drugs and pathways that induce cell death or cell cycle arrest independently of p53 deserves substantial attention. Within the scope of the parent project, this supplement to promote diversity in health-related research will be used to train the candidate, Kameza Harun to: 1: Synthesize oligonucleotides containing α/β ICLs; 2: Transfect cells with the α/β ICLs and extract proteins; 3: Validate the downstream signaling molecules, such as cyclin B1/Cdk1, involved in the p21 signaling pathway triggered by the presence of either the α or β- ICL. Kameza’s long-term goal is to become a clinical researcher in oncology. The training and activities proposed will improve Kameza’s chances to access MD-PHD programs by fostering crucial technical and professional skills. As Kameza gains new exposure to the research environment, she will become more comfortable interacting with other scientists and sharing her work. She will be fully prepared to join a research laboratory. In order to further enhance Kameza’s competitiveness, she will present her research findings at conferences and publish at least one manuscript. She will also receive career advisement from Dr Edgardo Sanabria-Valentin, the PRISM Associate Program Director and Pre-Health Career Advisor. He will assist Kameza in considering long-term career goals and the skills needed to achieve them.