Fanconi Anemia (FA) is a rare autosomal recessive cancer susceptibility disorder characterized by development abnormalities, bone marrow failure, and cellular hypersensitivity to DNA crosslinking agents. The systematic study of cell lines derived from FA patients has led to the cloning of eight FA genes (A, C, DI/BRCA2, D2, E, F, G, L) and the elucidation of a novel DNA repair pathway (the Fanconi Anemia/BRCA pathway). The elucidation of this pathway had broad significance for the understanding of the pathogenesis of aplastic anemia and cancer in the general population.
The specific aims of this five year grant are to (i) identify the molecular sensor of the FA/BRCA pathway (ii) determine the structural etements of FANCD2 required for its functional interaction with BRCA2 in chromatin and required for its DNA repair activities, and (iii) evaluate the newly identified FA-I and FA-J complementation groups.
|Li, Heng; Lim, Kah Suan; Kim, Hyungjin et al. (2016) Allosteric Activation of Ubiquitin-Specific Proteases by Î²-Propeller Proteins UAF1 and WDR20. Mol Cell 63:249-60|
|Zhang, Haojian; Kozono, David E; O'Connor, Kevin W et al. (2016) TGF-Î² Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia. Cell Stem Cell 18:668-81|
|Kais, Zeina; Rondinelli, Beatrice; Holmes, Amie et al. (2016) FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair. Cell Rep 15:2488-99|
|Xie, Jenny; Kim, Hyungjin; Moreau, Lisa A et al. (2015) RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway. J Clin Invest 125:1523-32|
|Kim, Hyungjin; Dejsuphong, Donniphat; Adelmant, Guillaume et al. (2014) Transcriptional repressor ZBTB1 promotes chromatin remodeling and translesion DNA synthesis. Mol Cell 54:107-18|
|Wojtaszek, Jessica L; Wang, Su; Kim, Hyungjin et al. (2014) Ubiquitin recognition by FAAP20 expands the complex interface beyond the canonical UBZ domain. Nucleic Acids Res 42:13997-4005|
|Price, Brendan D; D'Andrea, Alan D (2013) Chromatin remodeling at DNA double-strand breaks. Cell 152:1344-54|
|O'Connor, Kevin W; Dejsuphong, Donniphat; Park, Eunmi et al. (2013) PARI overexpression promotes genomic instability and pancreatic tumorigenesis. Cancer Res 73:2529-39|
|Mistry, Helena; Hsieh, Grace; Buhrlage, Sara J et al. (2013) Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells. Mol Cancer Ther 12:2651-62|
|D'Andrea, Alan D (2013) BRCA1: a missing link in the Fanconi anemia/BRCA pathway. Cancer Discov 3:376-8|
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