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The Deubiquitinating Enzyme USP1 Regulates the Fanconi Anemia Pathway

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The Deubiquitinating Enzyme USP1 Regulates the Fanconi Anemia Pathway Molecular Cell, Vol. 17, 331–339, February 4, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.molcel.2005.01.008 The Deubiquitinating Enzyme USP1 Regulates the Fanconi Anemia Pathway Sebastian M.B. Nijman,1,3 Tony T. Huang,2,3 tion. MMC and DEB hypersensitivity is a hallmark of FA Annette M.G. Dirac,1,3 Thijn R. Brummelkamp,1 and is used as a diagnostic test in the clinic (Auerbach Ron M. Kerkhoven,1 Alan D. D’Andrea,2,* et al., 1989). and Rene´ Bernards1,* The genetic basis for FA is diverse, and evidence 1Division of Molecular Carcinogenesis and Center exists for at least 11 complementation groups (Levitus for Biomedical Genetics et al., 2004). FA is clinically related to various other The Netherlands Cancer Institute hereditary chromosomal instability syndromes, and re- Plesmanlaan 121 cent work has shown that the protein products mutated 1066 CX Amsterdam in Bloom Syndrome, Nijmegen Breakage Syndrome The Netherlands (NBS), Ataxia Telangiectasia (ATM), and Seckel Syn- 2 Department of Radiation Oncology drome (ATR) functionally intersect with the FA signaling Dana-Farber Cancer Institute pathway (Andreassen et al., 2004; Meetei et al., 2003b; Harvard Medical School Nakanishi et al., 2002; Taniguchi et al., 2002b). Further- Boston, Massachusetts 02115 more, hypomorphic mutations in the BRCA2 gene make up the Fanconi complementation group D1 (FANCD1) (Howlett et al., 2002). Summary Based on clinical, biochemical, and cellular pheno- types, the FA proteins appear to function in a common Protein ubiquitination and deubiquitination are dy- cellular signaling network. At least seven of these pro- namic processes implicated in the regulation of nu- teins, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, merous cellular pathways. Monoubiquitination of the and the ubiquitin E3 ligase FANCL form a nuclear multi- Fanconi anemia (FA) protein FANCD2 appears to be subunit complex that is critical for the monoubiquitina- critical in the repair of DNA damage because many of tion of the FANCD2 protein (de Winter et al., 2000; Gor- the proteins that are mutated in FA are required for don and Buchwald, 2003; Meetei et al., 2003a; Meetei FANCD2 ubiquitination. By screening a gene family et al., 2004; Pace et al., 2002). Indeed, functional loss RNAi library, we identify the deubiquitinating enzyme of any of these FA proteins abrogates S phase and DNA USP1 as a novel component of the Fanconi anemia damage-induced FANCD2 ubiquitination. pathway. Inhibition of USP1 leads to hyperaccumula- Upon monoubiquitination on Lys561, FANCD2 relocal- tion of monoubiquitinated FANCD2. Furthermore, izes to nuclear DNA damage foci, where it binds to USP1 physically associates with FANCD2, and the pro- BRCA1 and the RAD51 recombinase and colocalizes teins colocalize in chromatin after DNA damage. Fi- with FANCD1/BRCA2 (Taniguchi et al., 2002a; Wang et nally, analysis of crosslinker-induced chromosomal al., 2004). It is thought that these nuclear foci mark the aberrations in USP1 knockdown cells suggests a role sites of DNA damage-induced double-strand breaks (DSB) in which DNA is repaired by means of homologous in DNA repair. We propose that USP1 deubiquitinates recombination. A role for FANCD2 and BRCA1 in ho- FANCD2 when cells exit S phase or recommence cy- mologous recombination is also suggested by their cling after a DNA damage insult and may play a critical presence at sites of meiotic recombination in spermato- role in the FA pathway by recycling FANCD2. genesis (Garcia-Higuera et al., 2001). Although the monoubiquitination of FANCD2 appears to be a critical Introduction event in efficient DNA repair, the exact molecular func- tion of FANCD2 is poorly understood. Maintenance of genomic integrity is critical in the protec- As mentioned, FANCD2 is also monoubiquitinated tion against malignant transformation. Genetic disor- during S phase, and this event is required for normal ders that perturb the repair of DNA damage, induced progression through this cell cycle phase. The monoubi- by either exogenous agents or endogenous events, of- quitinated form of FANCD2 (FANCD2-L) disappears ten lead to increased cancer susceptibility. One such when cells exit S phase and is transiently present in disorder is Fanconi anemia (FA), a rare syndrome with cells that have been exposed to DNA damage (Garcia- predisposition to a variety of malignancies (D’Andrea, Higuera et al., 2001; Taniguchi et al., 2002a). Both forms 2003). Genes mutated in FA have also been implicated of FANCD2 are stable and not subject to proteasomal in the carcinogenesis of sporadic tumors, underscoring degradation, indicating that the monoubiquitination the broad relevance of studying rare human genetic does not serve to target FANCD2-L for degradation. diseases (Taniguchi et al., 2003; Tischkowitz et al., 2003). Instead, it is more likely that a deubiquitinating enzyme At the cellular level, FA is characterized by chromo- (DUB) removes the ubiquitin moiety after DNA damage somal instability and hypersensitivity to DNA-crosslink- is repaired, and cells resume cycling. Like protein phos- ing agents, such as mitomycin C (MMC), cisplatin, di- phorylation, ubiquitination is dynamic and reversible, poxybutane (DEB), and to a lesser extent, ionizing radia- involving numerous ubiquitin-conjugating enzymes and DUBs (Chung and Baek, 1999; D’Andrea and Pellman, *Correspondence: [email protected] (A.D.D.); r.bernards@ 1998; Kim et al., 2003; Shackelford and Pagano, 2004; nki.nl (R.B.) Wilkinson, 2000). Homology searches in human genome 3 These authors contributed equally to this work. databases have yielded approximately 60 distinct genes Molecular Cell 332 coding for (putative) DUBs. Although DUBs have been cells with the four shRNA vectors and an expression functionally linked with various pathways and pro- vector containing a green fluorescent protein tagged cesses, surprisingly few mammalian DUB substrates version of USP1 (GFP-USP1). As expected, all four have been identified (Brummelkamp et al., 2003; Cum- shRNA vectors efficiently suppressed GFP-USP1 ex- mings et al., 2004; Graner et al., 2004; Kovalenko et al., pression (Figure 2C). 2003; Li et al., 2002; Trompouki et al., 2003). To study To study endogenous USP1 protein, a polyclonal anti- the role of these enzymes in specific pathways, we have serum directed against the N terminus of USP1 was constructed a library of 220 independent vectors ex- generated (see Experimental Procedures) and tested on pressing short hairpin RNAs (shRNA) targeting 55 human synthetic siRNA transfected or control HEK293 cells. DUBs. Using this library, we have previously identified Cells were also treated with the S phase inhibitor hy- the familial tumor suppressor CYLD as a negative regu- droxyurea (HU) to induce monoubiquitinated FANCD2. lator of TRAF2 poly-ubiquitination (Brummelkamp et al., Two bands present in the control lanes were efficiently 2002b; Brummelkamp et al., 2003). Here, we identify the downregulated in lysates derived from the USP1 siRNA- deubiquitinating enzyme USP1 as a novel component transfected cells (Figure 2D, upper panel). As expected, of the FA pathway and propose that USP1 is the enzyme the observed USP1 downregulation correlated with the that deubiquitinates FANCD2. upregulation of FANCD2-L (Figure 2D, lower panel). The predicted molecular weight of endogenous, full-length Results USP1 is 88 kDa, corresponding to the slower migrating USP1 species detected by Western blot and consistent Identification of USP1 as a Regulator with the size of ectopically expressed USP1 (see Figure of FANCD2 Monoubiquitination 3D, lower panel). The faster migrating band is likely a Previous experiments have indicated that during normal proteolytic fragment of USP1. We conclude that in our cell cycle progression, FANCD2 ubiquitination is dy- experiments, both ectopically expressed and endoge- namic (Taniguchi et al., 2002a). Therefore, we reasoned nous USP1 protein are efficiently inhibited by RNA inter- that inhibition of a DUB that cleaves the ubiquitin moiety ference. from FANCD2 would lead to an overall increase of Because FANCD2 monoubiquitination is activated in FANCD2-L (the monoubiquitinated isoform of FANCD2) S phase, we investigated whether USP1 inhibition re- in asynchronous cycling cells. To identify DUBs that sulted in an altered cell cycle distribution or S phase delay. We retrovirally transduced U2-OS cells with a have this effect on FANCD2 ubiquitination, we employed knockdown vector targeting USP1. After selection with the DUB gene family RNA interference library, previously puromycin, the cells were synchronized using a double- generated in our laboratory (Brummelkamp et al., 2003). thymidine block. Cells were released and samples for The library currently consists of 55 pools of 4 indepen- FACS and protein analysis were taken at the indicated dent shRNA-encoding plasmids targeting 55 DUBs for time points. Propidium-iodide (PI) staining of nuclei and suppression by RNA interference (Figure 1A and see subsequent FACS analysis indicated that cell cycle dis- Supplemental Table S1 at http://www.molecule.org/cgi/ tribution and S phase progression of USP1 knockdown content/full/17/3/331/DC1/). We electroporated each cells was unaffected, suggesting that USP1 inhibition pool of DUB knockdown vectors separately in U2-OS does not activate a cell cycle checkpoint (Figure 2E). cells and selected for shRNA expression. After 72 hr, Furthermore, although FANCD2-L levels decreased sig- we analyzed cell lysates by Western blot with an anti- nificantly
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