Differential Regulation of JAMM Domain Deubiquitinating Enzyme Activity within the RAP80 Complex

Patterson-Fortin, Jeffrey; Shao, Genze; Bretscher, Heidi; Messick, Troy E.; Greenberg, Roger A.

doi:10.1074/jbc.m110.135319

Cited by 69 publications

(94 citation statements)

References 49 publications

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“…The ABRO1/BRISC complex appears to associate with the COP9 signalosome (14). Recently, it was also suggested that BRISC deficiency enhances formation of the BRCA1-Rap80 interaction and increased BRCA1 levels at the DNA damage sites (33,36). However, the exact role of the ABRO1/BRISC complex needs further investigation to be understood.…”

Section: Nba1-bre Interaction Stabilizes Brcc36-containing Complexesmentioning

confidence: 98%

“…Although the significance of the similarities is not completely understood, it is likely that the complex is formed to facilitate the DUB activity of BRCC36. Indeed, recently it was shown that the presence of Abraxas, BRE, NBA1, and Rap80 is required for BRCC36 DUB activity in the BRCA1 A complex (33,36). For ABRO1/BRISC complex, ABRO1 dimerization with BRCC36 is required for BRCC36 to display a minimal DUB activity (19).…”

Section: Nba1-bre Interaction Stabilizes Brcc36-containing Complexesmentioning

confidence: 99%

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NBA1/MERIT40 and BRE Interaction Is Required for the Integrity of Two Distinct Deubiquitinating Enzyme BRCC36-containing Complexes

Kim

Castillo

et al. 2011

Journal of Biological Chemistry

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BRCC36-deubiquitinating enzyme (DUB) forms two different complexes through interactions with two different adaptor proteins Abraxas and ABRO1 in cells.Abraxas mainly localizes in the nucleus, mediating the interaction of BRCC36 with BRCA1. ABRO1 is mainly localized in the cytoplasm. Because it lacks the BRCA1-interacting motif, the ABRO1 complex does not interact with BRCA1. Both BRCC36-containing complexes contain common components including BRE and NBA1/MERIT40. Here, we found that the two complexes are assembled in a similar manner and NBA1 and BRE interaction is critical for maintaining the integrity of both of the complexes. Knockdown of NBA1 or BRE leads to decreased levels of components of the two BRCC36-containing complexes. We provided evidence that NBA1 interacts with BRE through a C-terminal conserved motif of the NBA1 protein and a C-terminal UEV domain of the BRE protein. Furthermore, the NBA1-BRE interaction is required for cellular resistance to ionizing irradiation and NBA1's role in recruiting BRCA1 to DNA damage sites. Together, these studies reveal critical interactions required for the formation and function of BRCC36-containing DUB complexes.Modification of proteins by the covalent attachment of ubiquitin (Ub) 2 to the lysine (Lys) residue of a target protein is a key regulatory mechanism of many cellular processes including the DNA damage response (1, 2). In response to ionizing irradiation, ubiquitination occurs at DNA damage sites in a central DNA damage kinases ATM/ATR-dependent manner (3). Ubiquitin Lys63 (K63) polyubiquitin chain linkages play important roles in the recruitment of repair factors in the DNA damage response (3). K63-linked polyubiquitin chains are assembled through a conserved heterodimer of an E2 complex composed of a catalytically active Ubc13 subunit and its inactive sequence homolog Mms2 that lacks the enzymatic active site (4, 5). The formation of K63-polyubiquitins at DNA damage sites depends on two E3 ligases RNF8 and RNF168 (3,6). In addition, a HECT domain-containing E3 ligase HERC2 is also involved in facilitating the formation of K63-linked ubiquitin chains (7).Deubiquitinating enzymes (DUBs) catalyze the removal of Ub from Ub-conjugated substrate proteins and it has become increasingly obvious that Ub deconjugation plays important roles in regulating Ub-dependent pathways (8, 9). BRCC36 is a member of a small family of DUBs containing JAMM/MPNϩ domain proteins, which are Zn 2ϩ -binding metalloproteases (10 -12). It selectively cleaves K63-linked polyubiquitin (12-14), and is required for proper checkpoint regulation in response to DNA damage (13,(15)(16)(17). It plays an important role in recruiting BRCA1 to DNA damage sites, as BRCC36 deficiency leads to decreased BRCA1 accumulation at DNA damage sites (3).BRCC36 is a component of the BRCA1 A complex (13, 17, 18). The BRCA1 A complex contains at least five different components, Abraxas, NBA1/MERIT40, BRE, Rap80, and BRCC36. It associates with BRCA1 through an interaction of Abraxas with the BRCA1 C-termina...

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Section: Nba1-bre Interaction Stabilizes Brcc36-containing Complexesmentioning

confidence: 98%

Section: Nba1-bre Interaction Stabilizes Brcc36-containing Complexesmentioning

confidence: 99%

NBA1/MERIT40 and BRE Interaction Is Required for the Integrity of Two Distinct Deubiquitinating Enzyme BRCC36-containing Complexes

Kim

Castillo

et al. 2011

Journal of Biological Chemistry

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“…Although the regulatory basis of its DUB activity is beginning to be understood (3)(4)(5)(6)34), it has remained unknown whether the BRCC36 ubiquitin hydrolyzing activity plays a role in mammalian DNA damage responses. In this study, we have systematically examined, by adopting both RNAi and genome editing approaches, whether BRCC36 and its DUB may be functionally important in driving cellular response to DSBs.…”

Section: Discussionmentioning

confidence: 99%

The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair

Ng¹,

Wei

Lan

et al. 2016

Journal of Biological Chemistry

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Multisubunit protein assemblies offer integrated functionalities for efficient cell signal transduction control. One example of such protein assemblies, the BRCA1-A macromolecular complex, couples ubiquitin recognition and metabolism and promotes cellular responses to DNA damage. Specifically, the BRCA1-A complex not only recognizes Lys 63 -linked ubiquitin (K63-Ub) adducts at the damaged chromatin but is endowed with K63-Ub deubiquitylase (DUB) activity. To explore how the BRCA1-A DUB activity contributes to its function at DNA double strand breaks (DSBs), we used RNAi and genome editing approaches to target BRCC36, the protein subunit that confers the BRCA1-A complex its DUB activity. Intriguingly, we found that the K63-Ub DUB activity, although dispensable for maintaining the integrity of the macromolecular protein assembly, is important in enforcing the accumulation of the BRCA1-A complex onto DSBs. Inactivating BRCC36 DUB attenuated BRCA1-A functions at DSBs and led to unrestrained DSB end resection and hyperactive DNA repair. Together, our findings uncover a pivotal role of BRCC36 DUB in limiting DSB processing and repair and illustrate how cells may physically couple ubiquitin recognition and metabolizing activities for fine tuning of DNA repair processes. Active hydrolysis of ubiquitin polymers by deubiquitylases (DUBs)2 has emerged as important biochemical processes that underlie diverse signal transduction pathways, including cell responses to DNA damage (1). To date, around 94 human DUBs have been identified and are classified into five families: ubiquitin C-terminal hydrolases, ubiquitin-specific proteases, ovarian tumor proteases, Josephins, and JAB1/MPN/MOV4 metalloproteases. Notably, the JAB1/MPN/MOV4 metalloprotease family members are zinc-dependent metalloproteases, and the other families are cysteine proteases (1).BRCC36, originally reported as the BRCA1/BRCA2-containing complex subunit 36 (2), is endowed with DUB activity for lysine 63-linked ubiquitin polymers (K63-Ub). BRCC36 DUB relies on its zinc-dependent JAB1/MPN/MOV4 metalloprotease domain (3) and its interaction with Abraxas/KIAA0157 (3-5). Although BRCC36 forms distinct nuclear and cytoplasmic complexes (5, 6) and plays pleiotropic roles during cell proliferation, the K63-Ub DUB is arguably best known for its strong links with the breast and ovarian susceptible gene product BRCA1 in DNA damage responses (DDRs). Indeed, BRCC36 resides within the BRCA1-A macromolecular protein complex, which comprises the ubiquitin-binding protein RAP80, BRCC45/BRE, Abraxas/CCDC98, Merit40/NBA1, and BRCA1. The BRCA1-A complex is targeted to chromatin domains surrounding DNA double strand breaks (DSBs) by the ubiquitin-binding protein RAP80, which preferentially binds to K63-Ub adducts generated by the ubiquitin-conjugating enzyme UBC13 (3, 7-12). Abraxas plays a major scaffolding role to support the integrity of the BRCA1-A assembly and directly anchors the tumor suppressor BRCA1 via a phosphorylation-dependent interaction (13-15). Indeed, BRCA1, via it...

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“…The BRCA1 A complex contains at least five different components: Rap80, Abraxas, NBA1 (also known as MERIT40), BRE (also known as BRCC45) and BRCC36 [32,[35][36][37][38][39][40][41]. Abraxas interacts with the BRCT domains of BRCA1 through a phospho-serine group (p-S406) at the C-terminus of Abraxas, and mediates the interaction of the A complex with BRCA1.…”

Section: Brca1-a Complex Is a Deubiquitinating (Dub) Complexmentioning

confidence: 99%

BRCA1 tumor suppressor network: focusing on its tail

Wang

2012

Cell & Bioscience

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Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer. BRCA1 plays critical roles in the DNA damage response that regulates activities of multiple repair and checkpoint pathways for maintaining genome stability. The BRCT domains of BRCA1 constitute a phospho-peptide binding domain recognizing a phospho-SPxF motif (S, serine; P, proline; × varies; F, phenylalanine). The BRCT domains are frequently targeted by clinically important mutations and most of these mutations disrupt the binding surface of the BRCT domains to phosphorylated peptides. The BRCT domain and its capability to bind phosphorylated protein is required for the tumor suppressor function of BRCA1. Through its BRCT phospho-binding ability BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP. The A, B and C complexes, at lease partially undertake BRCA1's role in mechanisms of cell cycle checkpoint and DNA repair that maintain genome stability, thus may play important roles in BRCA1's tumor suppressor function.Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer [1,2]. BRCA1 plays critical roles in a number of diverse cellular processes that ensure genome integrity and the increase risk of breast and ovarian cancer caused by mutation of BRCA1 has been attributed to increased genomic instability. To safeguard genome, cells have evolved a defensive mechanism, called the DNA damage response (DDR), to coordinate multiple cellular responses including DNA repair, cell cycle checkpoint regulation, transcription, senescence or apoptosis etc., to counteract genotoxic stress [3][4][5][6]. BRCA1 appears to act as a central mediator of the cellular response to DNA damage that regulates the activities of multiple repair and checkpoint pathways [3,5,[7][8][9][10]. BRCA1 is a substrate of the central DNA damage response kinases ATM/ATR that control the DDR. It is required for homology directed repair, a pathway that facilitates error-free repair of double-strand breaks (DSBs) and resolution of stalled DNA replication forks through homologous recombination (HR) [9][10][11] as well as postreplicative repair in response to UV damage [12]. Recently it is suggested that much of BRCA1's role in maintaining genome stability is accounted for by its role in maintaining heterochromatin integrity via H2A ubiquitination [13].BRCA1 associates with multiple repair proteins and cell cycle regulators and such a capability to form multiple protein complexes contributes to its role in maintaining chromosome stability and tumor suppression (Figure 1). BRCA1 is a large protein of 1,863 amino acids. It contains two important domains at each end of the protein, a RING domain at the N-terminus and two BRCT domains at the C-terminus. Many clinically important mutations of BRCA1 gene frequently target these two domains. BRCA1 dimerizes with BARD1 through the RING domain present on each or the protein, forming...

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Differential Regulation of JAMM Domain Deubiquitinating Enzyme Activity within the RAP80 Complex

Cited by 69 publications

References 49 publications

NBA1/MERIT40 and BRE Interaction Is Required for the Integrity of Two Distinct Deubiquitinating Enzyme BRCC36-containing Complexes

NBA1/MERIT40 and BRE Interaction Is Required for the Integrity of Two Distinct Deubiquitinating Enzyme BRCC36-containing Complexes

The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair

BRCA1 tumor suppressor network: focusing on its tail

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