NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control

Wang, Bin; Hurov, Kristen E.; Hofmann, Kay; Elledge, Stephen J.

doi:10.1101/gad.1770309

Cited by 159 publications

(199 citation statements)

References 43 publications

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“…In each instance, ubiquitylation of a protein associated with DNA repair is essential for its of any of the members of the complex results in failure of the other constituents to form DSB-associated foci, and increased sensitivity to ionizing radiation. Although structural evidence is needed to determine the actual degree of similarity to the proteasome, it is intriguing that multiple ubiquitin-binding domains would be present within the RAP80 complex (Wang et al, 2009). Perhaps these domains regulate BRCC36 catalytic activity or, alternatively, modulate the avidity of the complex for ubiquitin chains at DSBs.…”

Section: Connections Between Pikk Activity and Ubiquitylationmentioning

confidence: 99%

“…Bioinformatic analysis suggests similarity of the RAP80 core complex to the lid domain within the 19S subunit of the 26S proteasome (Wang et al, 2009). BRCC36 is a member of the JAMM family of metalloprotease DUB enzymes, and mutation of the zinc-binding residues results in increased sensitivity to DSBs, an impaired G2 checkpoint, and elevated levels of conjugated ubiquitin at DSBs (Shao et al, 2009a,b).…”

Section: Evidence For Ubiquitin Recognition At Dsbsmentioning

confidence: 99%

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The ubiquitin landscape at DNA double-strand breaks

Messick¹,

Greenberg²

2009

J Exp Med

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Section: Connections Between Pikk Activity and Ubiquitylationmentioning

confidence: 99%

Section: Evidence For Ubiquitin Recognition At Dsbsmentioning

confidence: 99%

The ubiquitin landscape at DNA double-strand breaks

Messick¹,

Greenberg²

2009

J Exp Med

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“…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).…”

mentioning

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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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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“…The BRCA1-A complex contains many subunits, including a coiled coil domain-containing protein (CCDC98/ABRAXAS), the BRCA1/BRCA2-containing complex subunit 45/brain and reproductive organ-expressed protein (BRCC45/BRE), the BRCA1/BRCA2-containing complex subunit 36 (BRCC36), mediator of RAP80 interactions and targeting subunit of 40/new component of the BRCA1-A complex (MERIT40/NBA1), and breast cancer 1 (BRCA1; refs. [6][7][8][9][10][11][12][13][14]. This recruitment is required for the activity of BRCA1 at the DNA damage checkpoint and for DNA repair.…”

Section: Introductionmentioning

confidence: 99%

“…Receptor-associated protein 80 (RAP80) plays an important role in signal transduction in the DNA damage response by recruiting the BRCA1-A complex to DNA damage sites in a lysine 63-mediated polyubiquitin-binding dependent manner (6)(7)(8)(9)(10)(11)(12)(13)(14). The BRCA1-A complex contains many subunits, including a coiled coil domain-containing protein (CCDC98/ABRAXAS), the BRCA1/BRCA2-containing complex subunit 45/brain and reproductive organ-expressed protein (BRCC45/BRE), the BRCA1/BRCA2-containing complex subunit 36 (BRCC36), mediator of RAP80 interactions and targeting subunit of 40/new component of the BRCA1-A complex (MERIT40/NBA1), and breast cancer 1 (BRCA1; refs.…”

Section: Introductionmentioning

confidence: 99%