Article

The Deubiquitinating Enzyme USP1 Regulates the Fanconi Anemia Pathway

Harvard University, Cambridge, Massachusetts, United States
Molecular Cell (Impact Factor: 14.02). 03/2005; 17(3):331-9. DOI: 10.1016/j.molcel.2005.01.008
Source: PubMed

ABSTRACT

Protein ubiquitination and deubiquitination are dynamic processes implicated in the regulation of numerous cellular pathways. Monoubiquitination of the Fanconi anemia (FA) protein FANCD2 appears to be critical in the repair of DNA damage because many of the proteins that are mutated in FA are required for FANCD2 ubiquitination. By screening a gene family RNAi library, we identify the deubiquitinating enzyme USP1 as a novel component of the Fanconi anemia pathway. Inhibition of USP1 leads to hyperaccumulation of monoubiquitinated FANCD2. Furthermore, USP1 physically associates with FANCD2, and the proteins colocalize in chromatin after DNA damage. Finally, analysis of crosslinker-induced chromosomal aberrations in USP1 knockdown cells suggests a role in DNA repair. We propose that USP1 deubiquitinates FANCD2 when cells exit S phase or recommence cycling after a DNA damage insult and may play a critical role in the FA pathway by recycling FANCD2.

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    • "So far, however, just several studies showed the limited understanding of the DDR roles for DUBs that mediate the processing and removal of ubiquitin . Although these DUBs have been previously suggested DDR connections (Clerici et al., 2014; Huang et al., 2006; Jacq et al., 2013; Nakada et al., 2010; Nicassio et al., 2007; Nijman et al., 2005; Nishi et al., 2014; Wiener et al., 2012), all of them were not directly involved in DNA end resection. The genetic screen in search of DUBs that are involved in DDR showed that USP4 perhaps is involved in DDR, but the detailed function and mechanism is not clear (Nishi et al., 2014). "
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    • "Polyubiquitin chains can extend from any of the seven lysine residues of ubiquitin itself, and diversity is further amplified by branching and the combinatorial possibilities of these varied linkages (Komander and Rape, 2012). These modifications are important in targeting proteins to the proteasome (Hershko et al., 1982), as well as in an expansive set of non-degradative roles: regulating DNA repair (Nijman et al., 2005), signaling, transcription (Kö hler et al., 2010;Samara et al., 2010), cell-cycle control (Teixeira and Reed, 2013), mitochondrial integrity (Bingol et al., 2014), and the generation and recycling of free ubiquitin (Turcu and Wilkinson, 2009). A large set of $95 known deubiquitinases (DUBs) comprising five families regulates specific removal of ubiquitin. "
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    • "The deubiquitinating enzyme USP1 regulates the level of FANCD2-Ub (Nijman et al., 2005). USP1 associates with its activating factor UAF1, and the USP1-UAF1 complex removes monoubiquitin from FANCD2 to complete the repair (Cohn et al., 2007) (Fig. 1D). "
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