Genome Stability Regulation by the Nuclear Pore-Chromosome Axis and Defects in Tumor Cells

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Project Summary The applicant, Veronica Rodriguez-Bravo, is committed to a long-lasting career in cancer research. Her goal is to become an independent investigator to study genome stability maintenance mechanisms regulated by nuclear pores (NPCs) and the mitotic checkpoint and the impact of defects on cancer. Veronica's three-year proposal will allow her to acquire skills to rigorously study NPC regulation in non- tumor and tumor cells and professional abilities necessary to become a successful independent group leader in the current challenging funding environment for young investigators. The scientific proposal aims to study the molecular and cellular details of the NPC-mitotic checkpoint axis that controls chromosomal stability and how errors impact tumor and non-tumor cells. Specifically, the proposed Aims seek to obtain mechanistic insights into how human cells integrate signals from the nuclear periphery (NPCs) and from mitotic chromosomes to protect genome integrity and examine how failure of these pathways contribute to chromosomal and NPC defects found in human cancers. Aim 1 will study the redundant regulation of Mad1, a key mitotic checkpoint protein, recruitment to chromosomes in mitosis and consequences of defects for tumor and non-tumor cells. Aim 2 will analyze the inter-connection and regulation of the NPC components implicated in the pre-mitotic signaling necessary for high fidelity mitosis. Aim 3 will examine how errors affecting the mitotic and the NPC signaling impact chromosomal stability, tumor cell division and survival and how weaknesses in tumor cells can be exploited for potential future targeted therapies. This proposal will generate essential data to understand how chromosomal and NPC signals feed to each other to ensure protection against chromosomal errors commonly found in cancer and also provide insights into how NPC defects and chromosomal abnormalities benefit tumor cell growth, survival and proliferation. With the mentorship of Dr. Jallepalli, and co-mentor Dr. Foley, the candidate will be able to expand her research skills, learn to write successful R01-type grants, produce preliminary new data for one or two manuscripts as corresponding author, secure a faculty position and interact with other scientists and collaborators to set the ground for a successful independent career. Importantly, she will acquire new technical skills learning novel methodologies of NPC sub-complexes purification from human cells to interrogate NPC composition and posttranslational modifications in tumor and non-tumor cells. In summary, Veronica and her mentors believe this proposal will be a critical opportunity to set the basis of her independent career as a biomedical cancer researcher and thus fulfill her dream of dedication to the study of cancer. In conclusion, this K award will be fundamental to provide Veronica protected time to successfully transition to research independence and contribute to the mission of the NIH and NCI.