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  • Ubiquitination is a covalent attachment of amino acid ubiqui


    Ubiquitination is a covalent attachment of 76 amino AMG 487 ubiquitin molecules to target proteins, either as single moieties (mono-ubiquitination) or as poly-ubiquitin chains of different structures, formed through isopeptide bonds between specific lysines of one ubiquitin residue (for example K48, K63 or others) and the C-terminus of the next ubiquitin subunit (Hospenthal et al., 2013, Komander and Rape, 2012, Kulathu and Komander, 2012). Ubiquitination occurs in a multi-step process involving three classes of enzymes: E1, E2, and E3, while deubiquitination is catalyzed by a group of proteases, collectively known as deubiquitinases (DUBs). The diverse enzymes regulating protein ubiquitination have a critical role in the regulation of protein stability and proteasomal degradation, in various cellular signaling cascades, transcriptional regulation, DNA repair, and in intracellular vesicle trafficking. Monoubiquitination of lysine 119 on histone H2A (H2AK119Ub) is an abundant histone modification that occupies up to 10% of cellular histone H2A and was the first documented case of protein ubiquitination (Goldknopf and Busch, 1977, Goldknopf et al., 1975). H2AK119Ub has been shown to play important roles in the regulation of essential genomic processes including transcription, cell-cycle progression, and DNA damage response (Frappier and Verrijzer, 2011, Panier and Durocher, 2009, Zhou et al., 2009). More recently, a novel K13/15 site on the histone H2A and its variant H2AX was shown to be the target of poly-ubiquitination during DNA damage response (Mattiroli et al., 2012). Ubiquitination events targeting other histones are also well characterized, for example histone H2B mono-ubiquitination that is an evolutionarily conserved marker of gene activation (H2BK120Ub) (Cao and Yan, 2012, Chandrasekharan et al., 2010), and histone H3 ubiquitination at multiple sites that was recently demonstrated to play a role in nucleosome assembly (Han et al., 2013). This review will focus on ubiquitin modifications of histone H2A, and specifically on histone H2A deubiquitinase enzymes (H2A-DUBs) that catalyze their removal from the chromatin: USP3, USP12, USP16, USP21, USP22 and USP44, BAP1, MYSM1 and BRCC36 (Fig. 1). We will review the biological roles of histone H2A ubiquitination in the regulation of gene expression and genetic stability, and subsequently cover the roles of H2A-DUBs in these pathways, including most recent developments and controversies in the field. The implications for the physiological roles of H2A-DUBs in mammalian stem cell maintenance, embryonic development and cellular differentiation, DNA damage response, and carcinogenesis will be discussed.
    Functions of histone H2A ubiquitination in mammalian cells
    Mammalian H2A-DUBs: emerging functions in cell biology and physiology Over 90 genes in the human genome are predicted to encode proteins with deubiquitinase enzymatic activity, and these are divided based on their sequence, structure and catalytic mechanism into five groups, namely ubiquitin specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), otubain proteases (OTUs), Machado-Joseph disease proteases (MJD), and JAMM-domain zinc metalloproteases (Clague et al., 2013, Komander et al., 2009, Nijman et al., 2005). With such a diversity of DUB enzymes and the current lack of methods for high-throughput identification of their substrates, characterization of enzymes that deubiquitinate histone H2A (H2A-DUBs) remains challenging. Nevertheless, based on biochemical in vitro assays, studies of protein localization and interaction with chromatin, and the analyses of the effects of protein overexpression and knockdown on histone ubiquitination levels, a number of proteins with H2A-DUB activity have been identified. These include members of the ubiquitin specific protease family USP3, USP12, USP16, USP21, USP22 and USP44, ubiquitin C-terminal hydrolase BAP1, and metalloproteases MYSM1 and BRCC36. DUBs that regulate the levels of H2A ubiquitination indirectly, for example USP7 and USP11 that affect the ubiquitination state and stability of PRC1 ubiquitin ligase (Maertens et al., 2010), are not included on our list and will not be discussed. Here we will summarize our current knowledge of the H2A-DUB activities in different cellular and physiological processes, namely stem cell maintenance, embryonic development and cellular differentiation, DNA damage response, and carcinogenesis. The domain structures of the H2A-DUBs are illustrated in Fig. 1, and a concise summary of other relevant information for each H2A-DUB is provided in Table 1, Table 2.