The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression

Castillo, Andy; Paul, Atanu; Sun, Baohua; Huang, Ting‐Hsiang; Wang, Yucai; Yazinski, Stephanie A.; Tyler, Jessica K.; Li, Lei; You, M. James; Zou, Lee; Yao, Jun; Wang, Bin

doi:10.1016/j.celrep.2014.06.050

Cited by 37 publications

(50 citation statements)

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“…Given the requirement of BRCC36 DUB in restraining HR repair ( Fig. 1) and that the BRCA1-A complex suppresses HR by modulating DNA end resection (23,24,30), we hypothesized that BRCC36 DUB may be important in blocking end resection events. To explore whether BRCC36 DUB modulates these early steps in HR repair, we examined the requirement of BRCC36 DUB in DSB end resection following cell irradiation.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…The physiologic importance of RAP80 complex ubiquitin foci association has remained elusive despite considerable investigation into DNA damage recognition mechanisms and its roles in cancer susceptibility (Nikkilä et al 2009;Antoniou et al 2010;Bolton et al 2010;Solyom et al 2012;Castillo et al 2014). This study reveals that a major function of the RAP80 complex is in DNA replication-associated repair.…”

Section: Discussionmentioning

confidence: 99%

“…Abraxas-null cells were sensitive to mitomycin C (MMC), and this was associated with reduced homologous recombination (HR) (Castillo et al 2014). BRCA1 has been reported to mediate several processes during ICL repair, where it functions in a HR-independent manner to promote unloading of the replication-initiating CMG complex during early stages of ICL recognition (Long et al 2014).…”

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confidence: 99%

“…Less well understood is MERIT40, which is not required for DUB activity in vitro but maintains interaction with the other subunits and is required for their stability in cells and localization to DNA damage foci Shao et al 2009;Wang et al 2009). In contrast to BRCA1 nullizygosity, deficiency in either RAP80 or Abraxas is well tolerated in mice Yin et al 2012;Castillo et al 2014), indicating that the most prominent component of DSB foci formation contributes to only a subset of BRCA1 DNA repair function (Huen et al 2009;Jiang and Greenberg 2015).…”

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confidence: 99%

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MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

et al. 2015

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MERIT40 is an essential component of the RAP80 ubiquitin recognition complex that targets BRCA1 to DNA damage sites. Although this complex is required for BRCA1 foci formation, its physiologic role in DNA repair has remained enigmatic, as has its relationship to canonical DNA repair mechanisms. Surprisingly, we found that Merit40 −/− mice displayed marked hypersensitivity to DNA interstrand cross-links (ICLs) but not whole-body irradiation. MERIT40 was rapidly recruited to ICL lesions prior to FANCD2, and Merit40-null cells exhibited delayed ICL unhooking coupled with reduced end resection and homologous recombination at ICL damage. Interestingly, Merit40 mutation exacerbated ICL-induced chromosome instability in the context of concomitant Brca2 deficiency but not in conjunction with Fancd2 mutation. These findings implicate MERIT40 in the earliest stages of ICL repair and define specific functional interactions between RAP80 complex-dependent ubiquitin recognition and the Fanconi anemia (FA)-BRCA ICL repair network.

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“…Indeed, Rap80 was recently shown to target BRCA1 to chromatin regions that are ϳ1 kb from break sites and to affect checkpoint responses and not DSB repair (30). Despite this relatively mild DNA repair phenotype, germ-line mutations exist in RAP80 and Abraxas in familial breast cancer, and numerous somatic mutations are observed in all members of the complex (28,31,32). Moreover, Rap80 and Abraxas knock-out mice are tumor-prone, with ϳ20% of mice developing lymphomas at 1 year of age (26 -28).…”

Section: Connecting Brca Network Biochemistry To the Ddrmentioning

confidence: 99%

Deciphering the BRCA1 Tumor Suppressor Network

Jiang

Greenberg

2015

Journal of Biological Chemistry

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The BRCA1 tumor suppressor protein is a central constituent of several distinct macromolecular protein complexes that execute homology-directed DNA damage repair and cell cycle checkpoints. Recent years have borne witness to an exciting phase of discovery at the basic molecular level for how this network of DNA repair proteins acts to maintain genome stability and suppress cancer. The clinical dividends of this investment are now being realized with the approval of first-in-class BRCAtargeted therapies for ovarian cancer and identification of molecular events that determine responsiveness to these agents. Further delineation of the basic science underlying BRCA network function holds promise to maximally exploit genome instability for hereditary and sporadic cancer therapy.The breast cancer early-onset genes BRCA1 and BRCA2 were discovered by positional cloning approaches in kindreds with a high prevalence of breast and ovarian cancer. The initial lack of clarity presented by the domain structure of the proteins was remedied by a series of discoveries that revealed the proteins biochemically interact in large nuclear foci in response to DNA damage and are required to execute homology-directed DNA repair and cell cycle checkpoints (1). These observations strongly suggested that a common function in genome integrity maintenance is necessary to suppress cancer. Subsequent advances in protein purification and mass spectrometry methodologies have led to the expansion of this concept with the discovery that at least 13 different tumor suppressor proteins interact with BRCA1 and BRCA2. Despite these striking similarities, a linear model of BRCA-dependent DNA repair and tumor suppression is challenged by multiple other observations, namely, only ϳ5% of each protein exists in association with the BRCA1-BRCA2 complex, and breast cancers occurring in individuals with germ-line BRCA1 or BRCA2 mutations typically display different histopathologies and gene expression profiles. Coupled with the realization that chemoresistance mechanisms in BRCA1 and BRCA2 mutant cancers also differ, these features have inspired a network model relating BRCA molecular function in DNA repair to tumor suppression. We highlight recent insights into the BRCA tumor suppressor network and stress the connections between basic molecular knowledge of these proteins and their roles in genome integrity, tumor suppression, and response to therapy.

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The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression

Cited by 37 publications

References 33 publications

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

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

MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

Deciphering the BRCA1 Tumor Suppressor Network

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