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Functional Roles of the E3 Ubiquitin Ligase UBR5 in Cancer Robert F

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Functional Roles of the E3 Ubiquitin Ligase UBR5 in Cancer Robert F Published OnlineFirst October 13, 2015; DOI: 10.1158/1541-7786.MCR-15-0383 Review Molecular Cancer Research Functional Roles of the E3 Ubiquitin Ligase UBR5 in Cancer Robert F. Shearer1,2, Mary Iconomou1,2, Colin K.W. Watts1, and Darren N. Saunders1,3 Abstract The Ubiquitin-Proteasome System (UPS) is an important tion of DNA damage response, metabolism, transcription, and regulator of cell signaling and proteostasis, which are essential apoptosis. Hence, UBR5 is a key regulator of cell signaling to a variety of cellular processes. The UPS is disrupted in many relevant to broad areas of cancer biology. However, the mech- diseases including cancer, and targeting the UPS for cancer anism by which UBR5 may contribute to tumor initiation and therapy is gaining wide interest. E3 ubiquitin ligases occupy progression remains poorly defined. This review synthesizes a key position in the hierarchical UPS enzymatic cascade, emerging insights from genetics, biochemistry, and cell biology largely responsible for determining substrate specificity and to inform our understanding of UBR5 in cancer. These molec- ubiquitin (Ub) chain topology. The E3 ligase UBR5 (aka ular insights indicate a role for UBR5 in integrating/coordinat- EDD1) is emerging as a key regulator of the UPS in cancer ing various cellular signaling pathways. Finally, we discuss and development. UBR5 expression is deregulated in many outstanding questions in UBR5 biology and highlight the need cancer types and UBR5 is frequently mutated in mantle cell to systematically characterize substrates, and address limita- lymphoma. UBR5 is highly conserved in metazoans, has tions in current animal models, to better define the role of unique structural features, and has been implicated in regula- UBR5 in cancer. Mol Cancer Res; 13(12); 1523–32. Ó2015 AACR. Ubiquitination and the Role of E3 Ubiquitin provides tissue specificity and fine-scale regulation of signaling Ligases outputs (6). Correct functioning of the UPS is essential for many cellular Ubiquitination is one of the most widespread and frequent processes such as cell-cycle progression and apoptosis. Conse- cellular posttranslational modifications (PTM) and is essential for quently, the UPS is the subject of intense interest for its therapeutic normal cellular functions. Ubiquitination can regulate protein potential in many diseases including cancer [reviewed elsewhere levels via degradation by the proteasome (1, 2), regulate protein– (8)]. Currently, only broad-acting proteasome inhibitors are in protein interactions, and modulating protein function and local- clinical use. Proteasome inhibitors bortezomib (Velcade) and ization (3, 4). The small protein modifier Ubiquitin (Ub) forms carfilzomib (Kyprolis) have reached phase II clinical trials for use an isopeptide bond with substrate proteins via acceptor lysine in mantle cell lymphoma (MCL) and multiple myeloma (9–12), residues in a hierarchical enzymatic reaction catalyzed by an E3 although use is associated with peripheral neuropathy (12, 13). Ub ligase (5). Much variety in Ub modification of substrate The E3 ligase modulator Lenalidomide (Revlimid, an analogue of proteins arises from the ability of Ub to form either single Thalidomide), is also used in treatment of multiple myeloma but conjugates (mono-ubiquitination) or chains (poly-ubiquitina- has associated resistance and toxicity (14). tion) after repeated rounds of Ub attachment (6). Further com- The UPS targets a large range of proteins with important roles in plexity and diversity in Ub PTMs is generated by variation in Ub cancer biology. Therapeutic benefit with reduced toxicity might be chain topology, depending on which Ub lysine residue is further obtained by targeting more specific aspects of the UPS. For ubiquitinated on the growing poly-Ub chain. Various poly-Ub example, Ub-specific proteases, an extensive class of de-ubiqui- chain topologies are known to effect different signaling outcomes tinating enzymes, have promise as therapeutic targets (15). Of via binding to specific adaptor proteins [reviewed elsewhere (4)]. comparable interest and specificity are the E3 Ub ligases, espe- Specificity of the Ubiquitin-Proteasome System (UPS) is largely cially as key proteins commonly associated with proliferation and determined by the approximately 617 (human) E3 Ub ligases (7), cell-cycle arrest (such as p53, p27, Cyclins, and NF-kB) are but significant pleiotropy and redundancy among E3 Ub ligases specifically regulated by these enzymes (16). One of the more intriguing members of the E3 ligase family is 1 UBR5 [Ubiquitin protein ligase E3 component n-recognin 5, also Kinghorn Cancer Centre, Garvan Institute of Medical Research, Dar- fi linghurst, Australia. 2St.Vincent's Clinical School, Faculty of Medicine, known as EDD (E3 identi ed by Differential Display), EDD1, University of New South Wales, Sydney, Australia. 3School of Medical HHYD, KIAA0896, or DD5]. UBR5 is highly conserved (17) and is Sciences, Faculty of Medicine, University of New South Wales, Sydney, essential for mammalian development (18). UBR5 is rarely Australia. mutated in healthy somatic tissues, but is mutated and/or over- Corresponding Author: Darren N. Saunders, School of Medical Sciences, Uni- expressed in cancer (19, 20). UBR5 is known to modulate the versity of New South Wales, Sydney, NSW 2052, Australia. Phone: 61-2- DNA damage response (DDR) and transcription (see below for 93852494; Fax: 61-2-92958100; E-mail: [email protected] detailed discussion), and emerging roles for UBR5 in a number of doi: 10.1158/1541-7786.MCR-15-0383 biologic contexts have been identified using high-throughput, Ó2015 American Association for Cancer Research. functional genomics screens. This review will summarize the www.aacrjournals.org 1523 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst October 13, 2015; DOI: 10.1158/1541-7786.MCR-15-0383 Shearer et al. characterized and emerging biologic roles of UBR5, its role in UBR5 is highly overexpressed in breast cancer at the mRNA level tumorigenesis, and its potential as a therapeutic target. with increases in UBR5 protein also evident in many samples (19). This indicates that regulation of UBR5 is likely at the Unique Genomic and Protein Structure of transcriptional level, though regulation of activity may also occur UBR5 through PTM. Many phosphorylation sites have been identified in UBR5 (see Fig. 1; refs. 34–41), and UBR5 is known to be a UBR5 is a homologue of hyperplastic discs (HYD), a Drosophila phosphorylation target of ATM (42), CHK (43), and ERK kinases melanogaster tumor suppressor (21). Mammalian UBR5 is a HECT (44). However, this phosphorylation has not as yet been directly (homologous to E6-associated protein at the carboxy-terminus) linked to UBR5 activity. E3 Ub ligase recognizing n-degrons (see Fig. 1; refs. 17, 22). The human UBR5 gene has 59 exons, encoding an approximately 10 UBR5 in Cancer kb mRNA and >300 kDa protein with widespread expression in various cell types. One splice variant (loss of nucleotides 884– A number of studies have implicated UBR5 in various aspects 901, removing amino-acid sequence VLLLPL) has been identified of cancer biology and many of the molecular functions of UBR5 in 26/26 cancer cell lines investigated (19), although numerous (e.g., DDR) are consistent with a role in cancer. Indeed, the fi other splice variants are predicted in genome databases. The Drosophila homologue Hyd was originally identi ed as a tumor fi structural/functional consequences of these variants are not suppressor gene (21). Human UBR5 was originally identi ed in a known. UBR5 is highly conserved, but appears to be restricted screen for progestin-regulated genes in breast cancer cells (17). fi to the metazoan lineage, and based on phylogenetic analysis is Ampli cation of UBR5 has been reported in breast and ovarian grouped in a distinct class of HECT ligases (Class IV; ref. 23). Class cancer, mostly in the form of allelic imbalance resulting in IV likely evolved from a common ancestral gene duplication and increased UBR5 mRNA levels (19). UBR5 is located at genomic includes UBR5/EDD and three other families that are highly locus 8q22.3 (17), just downstream from MYC (8q22.4) but fi divergent at the sequence level. UBR5 ampli cation is independent of microsatellites examined HECT E3 Ub ligases have a well characterized mechanism, in the more distal regions of the 8q arm (19). Provisional data forming a thio-ester linkage between Ub and the substrate pro- from The Cancer Genome Atlas (TCGA) clearly show UBR5 fi tein, a reaction highly dependent on a conserved cysteine within ampli cation to be a common alteration in many cancer types the HECT domain (24, 25). The catalytically active HECT domain (see Fig. 2A). UBR5 has been shown to mediate therapeutic of UBR5 is made up of N- and C-lobes separated by a linker resistance in ovarian cancer (20), likely through modulation of fi sequence as determined by high-resolution crystallography (26). the DDR (see below). UBR5 was also identi ed in a transposon However, the HECT domain of UBR5 has some unique structural mutagenesis screen for cooperating mutations and pathways in features compared with other HECT ligases. The C-lobe of the pancreatic adenocarcinoma (45). UBR5 HECT domain does not have a surface for noncovalent Perhaps the most convincing evidence yet for an integral role binding of Ub, and it is unclear if this exists in the N-lobe (a feature for UBR5 in cancer comes from a recent
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