Fanconi Anemia (FA) is an autosomal recessive cancer susceptibility disorder characterized by congenital abnormalities, bone marrow failure, and cellular hypersensitivity to DNA crosslinking agents. Nine FA genes have been cloned, and the nine encoded proteins (A, B, C, D1, D2, E, F, G, L) cooperate in a common cellular pathway, leading to the monoubiquitination of FANCD2 and its interaction in chromatin with FANCD1/BRCA2. Interestingly, a novel deubiquitinating enzyme, called USP1, deubiquitinates FANCD2 and shuts the pathway """"""""off """""""" Nijman et al, Molecular Cell 17: 331,2005). Little is known about the regulation of USP1, the other substrates of USP1, or the global cellular function of USP1 in DNA repair. Very recently, we have made two important observations about USP1. First, USP1 is rapidly degraded following DNA damage, resulting in the accumulation of FANCD2-Ub. This result suggests that FANCD2-Ub accumulation results from decreased deubiquitination as well as increased ubiquitination by the FA complex. Second, in addition to FANCD2-Ub, USP1 also deubiquitinates the processivity factor, PCNA, and thus regulates translesion DNA synthesis (TLS). This observation suggests a functional connection between the FA pathway and DNA replication by variant DNA polymerases in TLS. Based on these new observations, we propose the following three aims for the next five years.
In Specific Aim #1, we will examine the molecular mechanism of DNA damage-inducible USP1 degradation.
In Specific Aim #2, we will examine the cellular outcome of USP1 dysregulation (namely, the affect on FA pathway mediated and TLS-mediated DNA repair activity and mutation frequency). For this aim, we will use a newly-generated Usp1-deficient mouse model.
In Specific Aim #3, we will examine the monoubiquitination and deubiquitination of FANCD2 mutant polypeptides in vitro and in vivo. We will also determine the interaction of these FANCD2 mutant proteins with the FA complex and with USP1. Overall, we believe these studies will elucidate the cellular regulatory mechanisms which control the monoubiquitination state of key biological modulators, such as FANCD2. ? ? ?
| Rondinelli, Beatrice; Gogola, Ewa; Yücel, Hatice et al. (2017) EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nat Cell Biol 19:1371-1378 |
| 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 |
| 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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