Protein ubiquitination is an important regulator of cytokine-mediated signal transduction pathways and hematopoietic cell growth. Protein ubiquitination is controlled by the coordinate action of ubiquitin conjugating enzymes and deubiquitinating enzymes. During the last 10 years of this grant, our laboratory has examined the regulation of cytokine-mediated signal transduction events by sequential phosphorylation and ubiquitination of intracellular signaling proteins. Recently, my laboratory has made the surprising observation that another hematopoietic signaling pathway, the Fanconi Anemia (FA) Pathway, is also regulated by highly coordinated monoubiquitination and deubiquitination events. The six cloned FA genes (A, C, D2, E, F, and G) interact in a novel pathway. Five of the FA proteins (A, C, E, F, and G) assemble in a nuclear complex which is required for the monoubiquitination of the downstream FA protein, FANCD2 (Garcia-Higuera et al, Mol Cell, 2001). Disruption of this pathway leads to the characteristic clinical phenotype observed in FA, including developmental abnormalities, progressive bone marrow failure, and predisposition to acute myeloid leukemia. During the next five of years of support, our laboratory plans to (1) devise and employ an in vitro ubiquitination assay to determine the precise requirements for the monoubiquitination of the FANCD2 protein (2) analyze the enzyme(s) involved in the regulated deubiquitination of FANCD2 which occurs during the G2/M transition of the cell cycle or following repair of DNA damage and (3) examine the binding partners of the activated (monoubiquitinated) isoform of FANCD2. In the course of these experiments, we hope to determine novel protein regulators of in vivo hematopoietic stem cell growth and differentiation.
Karras, Georgios I; Yi, Song; Sahni, Nidhi et al. (2017) HSP90 Shapes the Consequences of Human Genetic Variation. Cell 168:856-866.e12 |
Mouw, Kent W; Goldberg, Michael S; Konstantinopoulos, Panagiotis A et al. (2017) DNA Damage and Repair Biomarkers of Immunotherapy Response. Cancer Discov 7:675-693 |
Rondinelli, Beatrice; Gogola, Ewa; YĆ¼cel, Hatice et al. (2017) EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nat Cell Biol 19:1371-1378 |
Li, Heng; Lim, Kah Suan; Kim, Hyungjin et al. (2016) Allosteric Activation of Ubiquitin-Specific Proteases by ?-Propeller Proteins UAF1 and WDR20. Mol Cell 63:249-260 |
Zhang, Haojian; Kozono, David E; O'Connor, Kevin W et al. (2016) TGF-? 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 |
Bluteau, Dominique; Masliah-Planchon, Julien; Clairmont, Connor et al. (2016) Biallelic inactivation of REV7 is associated with Fanconi anemia. J Clin Invest 126:3580-4 |
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 54:107-118 |
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 |
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