BRCA-dependent Mechanisms of Genome Maintenance and Repair

摘要

ABSTRACT DNA double-strand breaks (DSBs) are among the most deleterious of DNA lesions and, if not handled properly, can lead to gross chromosome aberrations, neoplastic transformation of cells, and tumorigenesis. The NCI-funded research program of the Unit Director Dr. Patrick Sung has focused on elucidating conserved homologous recombination (HR) mechanisms, by which DSBs are being faithfully repaired. Through a transdisciplinary approach encompassing biochemical reconstitution, biophysical analysis, structural biology, and cell-based investigations, the Sung laboratory has provided insights into critical steps of HR. The available experimental and intellectual framework ideally positions us to continue delineating the mechanistic intricacy of HR and DSB repair processes, to provide actionable information for explaining why HR gene mutations lead to genome instability, replication fork demise, neoplastic cell transformation, and cancer. As Research Associate Professor, I have been making contributions in elucidating the underlying mechanisms of three critical stages of HR, namely, RAD51 presynaptic filament assembly, DNA strand invasion, and repair DNA synthesis. I have also played a key role in the training and mentoring of graduate students and research fellows in the Sung laboratory. In this R50 Research Specialist Award application, I request salary support to enable me to help drive research endeavors directed at elucidating the multifaceted roles that the tumor suppressors BRCA1-BARD1, BRCA2, FANCJ, and their companion HR factors fulfill in the aforementioned stages of the HR process and in DNA replication fork preservation. As such, the R50 Research Specialist Award will not only help advance our research objectives, but will also exert a broader impact in the DNA repair and cancer biology fields as I continue to devise novel biochemical assays and systems reconstituted with purified HR factors to facilitate the studies of other laboratories, and will help identify novel targets and pathway pivot points to spur the development of small molecule compounds as chemical biology tools and potential cancer therapeutics. 【 I will continue to advise the Unit Director in all matters concerning the general directions of our research program, take on major responsibilities in mentoring and training of doctoral students and postdoctoral fellows, and act as the main conduit with intramural and extramural collaborators. I will serve as the corresponding author on studies in which I have played a leadership role, attend major conferences to disseminate my research findings, and develop a national reputation based on my own merit. 】