https://www.ncbi.nlm.nih.gov/gene/79184
"BRCC36 is a Key Player in Cellular Responses to DSBs
- Official Symbol BRCC3
- Official Full Name BRCA1/BRCA2-containing complex subunit 3.
- Gene type protein coding
- Also known as C6.1A; BRCC36; CXorf53
- Summary: This gene encodes a subunit of the BRCA1-BRCA2-containing complex (BRCC), which is an E3 ubiquitin ligase. This complex plays a role in the DNA damage response, where it is responsible for the stable accumulation of BRCA1 at DNA break sites. The component encoded by this gene can specifically cleave Lys 63-linked polyubiquitin chains, and it regulates the abundance of these polyubiquitin chains in chromatin. The loss of this gene results in abnormal angiogenesis and is associated with syndromic moyamoya, a cerebrovascular angiopathy. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 5. [provided by RefSeq, Jun 2011]
- Expression Ubiquitous expression in colon (RPKM 4.9), esophagus (RPKM 3.5) and 25 other tissues See more Orthologs mouse all
- Preferred Names
- lys-63-specific deubiquitinase BRCC36
- Names
- BRCA1-A complex subunit BRCC36
- BRCA1/BRCA2-containing complex subunit 36
- BRISC complex subunit BRCC36
lys-63-specific deubiquitinase BRCC36 isoform 2 [Homo sapiens]
NCBI Reference Sequence: NP_001018065.1
- Conserved Domains (1) summary
-
- cd08068
Location:13 → 267 - MPN_BRCC36; Mov34/MPN/PAD-1 family:
BRCC36, a subunit of BRCA1-A complexBRCC36 (BRCA1-A complex subunit BRCC36; - BRCA1/BRCA2-containing complex subunit
36; BRCA1/BRCA2-containing complex subunit 3; BRCC3; BRISC complex
subunit BRCC36; BRCC36 isopeptidase complex; Lys-63-specific
deubiquitinase BRCC36) and BRCC36-like domains are members of JAMM/MPN+
deubiquitinases (DUBs), possibly with Zn2+-dependent ubiquitin
isopeptidase activity. BRCC36 is part of the
BRCA1/BRCA2/BARD1-containing nuclear complex that displays an E3
ubiquitin ligase activity. It is targeted to DNA damage foci after
irradiation; RAP80 recruits the Abraxas-BRCC36-BRCA1-BARD1 complex to
DNA double strand breaks (DSBs) for DNA repair through specific
recognition of Lys 63-linked polyubiquitinated proteins by its tandem
ubiquitin-interacting motifs. A new protein, MERIT40 (mediator of RAP80
interactions and targeting 40 kDa), also named NBA1 (new component of
the BRCA1 A complex), exists in the same BRCA1-containing complex and is
essential for the integrity of the complex. There are studies
suggesting that MERIT40/NBA1 ties BRCA1 complex integrity, DSB
recognition, and ubiquitin chain activities to the DNA damage response.
It has also been shown that BRCA1-containing complex resembles the lid
complex of the 26S proteasome.
Region 13..267 /region_name="MPN_BRCC36" /note="Mov34/MPN/PAD-1 family: BRCC36, a subunit of BRCA1-A complex; cd08068" /db_xref="CDD:163699" Site order(33,122,124,132,135) /site_type="other" /note="MPN+ (JAMM) motif" /db_xref="CDD:163699" Site order(122,124,135) /site_type="other" /note="Zinc-binding site [ion binding]" /db_xref="CDD:163699"
- cd08068
- Knockdown of BRCC3 exerts an anti‑tumor effect on cervical cancer in vitro. Zhang F, et al. Mol Med Rep, 2018 Dec. PMID 30272359, Free PMC Article
- The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair. Ng HM, et al. J Biol Chem, 2016 Jul 29. PMID 27288411, Free PMC Article
- BRCC3 acts as a prognostic marker in nasopharyngeal carcinoma patients treated with radiotherapy and mediates radiation resistance in vitro. Tu Z, et al. Radiat Oncol, 2015 May 30. PMID 26024915, Free PMC Article
- BRCC3 mutations in myeloid neoplasms. Huang D, et al. Haematologica, 2015 Aug. PMID 26001790, Free PMC Article
- Downregulation of BRCA1-BRCA2-containing complex subunit 3 sensitizes glioma cells to temozolomide. Chai KM, et al. Oncotarget, 2014 Nov 15. PMID 25337721, Free PMC Article
GeneRIFs: Gene References Into Functions
- Luciferase reporter assay and in vitro rescue experiment confirmed that ANRIL promoted NLRP3 inflammasome activation by up-regulating BRCC3 expression via sponging miR-122-5p.
- Knockdown of BRCC3 in HeLa and SiHa cervical cancer cells revealed that BRCC3 interference inhibited the viability, in addition to the invasion and migration abilities, of cervical cancer cells via regulation of Snai family members and MMPs, which subsequently inhibit the progress of EMT.
- this study shows that mitochondrial DNA oxidation induces imbalanced activity of NLRP3/NLRP6 inflammasomes by activation of caspase-8 and BRCC36 in dry eye
- In late S/G2 phase, the DNA damage-responsive E3 ligase RNF8 conjugates K63-linked ubiquitin chains to tankyrase 1, while in G1 phase such ubiquitin chains are removed by BRISC, an ABRO1/BRCC36-containing deubiquitinase complex.
- 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.
- BRCC3 may play a role in B7-H3-induced 5-Fu resistance.
- BRCC3 inversely correlated with NPC overall and relapse-free survival. Its expression was higher in radioresistant NPC cells, where BRCC3 knockdown increased the cell survival fraction, attenuated DNA damage repair and resulted in G2/M cell cycle arrest.
- BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.
- KIAA0157 allosterically activates a cognate deubiquitinating enzyme (DUB) partner and implicates super dimerization as a new regulatory mechanism underlying BRCC36 DUB activity.
- upregulation of BRCC3 expression is associated with glioma.
"BRCC36 is a Key Player in Cellular Responses to DSBs
BRCC36, which
belongs to the JAMM (JAB1/MPN/Mov34 metallo-enzyme) family of DUBs,
is a lysine 63-ubiquitin (K63-Ub)-specific DUB and a member of two
protein complexes: the DNA damage-responsive BRCA1–RAP80 complex,
and the cytoplasmic BRCC36 isopeptidase complex (BRISC).
BRCC36 was initially isolated from a multi-protein complex containing the HR-promoting factors BRCA1, BRCA2 and Rad51 [145].
The interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein, targets a complex containing the BRCA1–BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and BRCC36 to MDC1–γH2AX-dependent lysine(6)- and lysine(63)-linked ubiquitin polymers at sites of DSBs [147].
Interestingly, it appears that concomitant and opposing RNF8–Ubc13 ubiquitin ligase and RAP80–BRCC36 ubiquitin hydrolysis activities are responsible for determining steady-state ubiquitin levels at DSB sites [148, 149].
BRCC36 was initially isolated from a multi-protein complex containing the HR-promoting factors BRCA1, BRCA2 and Rad51 [145].
The interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein, targets a complex containing the BRCA1–BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and BRCC36 to MDC1–γH2AX-dependent lysine(6)- and lysine(63)-linked ubiquitin polymers at sites of DSBs [147].
Interestingly, it appears that concomitant and opposing RNF8–Ubc13 ubiquitin ligase and RAP80–BRCC36 ubiquitin hydrolysis activities are responsible for determining steady-state ubiquitin levels at DSB sites [148, 149].
Recent discoveries
have shed some light on the mode-of-action of the BCC36-containing
complex. Thus, in striking contrast to other BRCA1-containing
complexes that are known to promote homology-directed repair, the
BRCA1–RAP80 complex restricts DNA end resection in S/G2 phase of
the cell cycle, thereby limiting HR.
Consequently, RAP80 or BRCC36 deficiency was found to result in elevated MRE11–CtIP-dependent 5′ DNA end resection with a concomitant increase in HR mechanisms that rely on 3′ single-stranded overhangs. In this way, the BRCA1–RAP80 complex limits nuclease activities at DSB sites, preventing excessive end resection and potentially deleterious homology-directed DSB repair mechanisms that can impair genome integrity [150].
Notably, the human BRCC36 gene is located at the Xq28 locus, a chromosomal break-point in patients with prolymphocytic T cell leukaemia [151].
Furthermore, BRCC36 is aberrantly expressed in the majority of breast tumours, indicating a potential role in the pathogenesis of this disease [145].
Taking these findings together, BRCC36 is clearly a key player in controlling cellular DSB responses through regulating the ubiquitylation status of repair factors at DNA damage sites."
Consequently, RAP80 or BRCC36 deficiency was found to result in elevated MRE11–CtIP-dependent 5′ DNA end resection with a concomitant increase in HR mechanisms that rely on 3′ single-stranded overhangs. In this way, the BRCA1–RAP80 complex limits nuclease activities at DSB sites, preventing excessive end resection and potentially deleterious homology-directed DSB repair mechanisms that can impair genome integrity [150].
Notably, the human BRCC36 gene is located at the Xq28 locus, a chromosomal break-point in patients with prolymphocytic T cell leukaemia [151].
Furthermore, BRCC36 is aberrantly expressed in the majority of breast tumours, indicating a potential role in the pathogenesis of this disease [145].
Taking these findings together, BRCC36 is clearly a key player in controlling cellular DSB responses through regulating the ubiquitylation status of repair factors at DNA damage sites."
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