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Protein

Lys-63-specific deubiquitinase BRCC36

Gene

BRCC3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Does not have activity toward 'Lys-48'-linked polyubiquitin chains. Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). In the BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double-strand breaks (DSBs) (PubMed:20656690). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:20656690, PubMed:24075985, PubMed:26344097, PubMed:26195665). Mediates the specific 'Lys-63'-specific deubiquitination associated with the COP9 signalosome complex (CSN), via the interaction of the BRISC complex with the CSN complex (PubMed:19214193). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985).12 Publications

Cofactori

Zn2+By similarityCuratedNote: Binds 1 zinc ion per subunit.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi122 – 1221Zinc; catalyticCurated
Metal bindingi124 – 1241Zinc; catalyticCurated
Metal bindingi135 – 1351Zinc; catalyticBy similarity

GO - Molecular functioni

  • enzyme regulator activity Source: MGI
  • metal ion binding Source: UniProtKB-KW
  • metallopeptidase activity Source: UniProtKB
  • polyubiquitin binding Source: UniProtKB
  • thiol-dependent ubiquitin-specific protease activity Source: UniProtKB

GO - Biological processi

  • cell division Source: UniProtKB-KW
  • double-strand break repair Source: UniProtKB
  • double-strand break repair via nonhomologous end joining Source: Reactome
  • G2 DNA damage checkpoint Source: UniProtKB
  • histone H2A K63-linked deubiquitination Source: UniProtKB
  • mitotic nuclear division Source: UniProtKB-KW
  • positive regulation of DNA repair Source: UniProtKB
  • protein K63-linked deubiquitination Source: UniProtKB
  • response to ionizing radiation Source: UniProtKB
  • response to X-ray Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Chromatin regulator, Hydrolase, Metalloprotease, Protease

Keywords - Biological processi

Cell cycle, Cell division, DNA damage, DNA repair, Mitosis, Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-5693565. Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
R-HSA-5693571. Nonhomologous End-Joining (NHEJ).
R-HSA-5693607. Processing of DNA double-strand break ends.
R-HSA-69473. G2/M DNA damage checkpoint.
SIGNORiP46736.

Protein family/group databases

MEROPSiM67.004.

Names & Taxonomyi

Protein namesi
Recommended name:
Lys-63-specific deubiquitinase BRCC36 (EC:3.4.19.-4 Publications)
Alternative name(s):
BRCA1-A complex subunit BRCC36
BRCA1/BRCA2-containing complex subunit 3
BRCA1/BRCA2-containing complex subunit 36
BRISC complex subunit BRCC36
Gene namesi
Name:BRCC3
Synonyms:BRCC36, C6.1A, CXorf53
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

HGNCiHGNC:24185. BRCC3.

Subcellular locationi

GO - Cellular componenti

  • BRCA1-A complex Source: UniProtKB
  • BRISC complex Source: UniProtKB
  • cytoplasm Source: UniProtKB
  • nuclear ubiquitin ligase complex Source: UniProtKB
  • nucleoplasm Source: HPA
  • nucleus Source: UniProtKB
  • spindle pole Source: UniProtKB-SubCell
  • ubiquitin ligase complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Nucleus

Pathology & Biotechi

Involvement in diseasei

A chromosomal aberration involving BRCC3 is a cause of pro-lymphocytic T-cell leukemia (T-PLL). Translocation t(X;14)(q28;q11) with TCRA.

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi23 – 231L → R: Abolishes localization to sites of DNA damage and interaction with FAM175B; UIMC1; SHMT2; BRE and BABAM1; when associated with R-27. 1 Publication
Mutagenesisi27 – 271L → R: Abolishes localization to sites of DNA damage and interaction with FAM175B; UIMC1; SHMT2; BRE and BABAM1; when associated with R-23. 1 Publication
Mutagenesisi122 – 1243HSH → QSQ: Abolishes metalloprotease activity and function in DNA repair. 4 Publications
Mutagenesisi122 – 1221H → Q: Loss of deubiquitinase activity. 1 Publication
Mutagenesisi278 – 2781A → R: Abolishes interaction with UIMC1 and SHMT2. 1 Publication

Keywords - Diseasei

Proto-oncogene

Organism-specific databases

MalaCardsiBRCC3.
Orphaneti280679. Moyamoya disease - short stature - facial dysmorphism - hypergonadotropic hypogonadism.
PharmGKBiPA134922847.

Polymorphism and mutation databases

BioMutaiBRCC3.
DMDMi20532383.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemoved1 Publication
Chaini2 – 316315Lys-63-specific deubiquitinase BRCC36PRO_0000213967Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylalanine1 Publication
Modified residuei258 – 2581PhosphoserineCombined sources

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP46736.
MaxQBiP46736.
PaxDbiP46736.
PeptideAtlasiP46736.
PRIDEiP46736.

PTM databases

iPTMnetiP46736.
PhosphoSiteiP46736.

Expressioni

Tissue specificityi

Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Aberrantly expressed in the vast majority of breast tumors.1 Publication

Gene expression databases

BgeeiENSG00000185515.
CleanExiHS_BRCC3.
ExpressionAtlasiP46736. baseline and differential.
GenevisibleiP46736. HS.

Organism-specific databases

HPAiHPA048737.

Interactioni

Subunit structurei

Component of the ARISC complex, at least composed of UIMC1/RAP80, FAM175A/Abraxas, BRCC3/BRCC36, BRE/BRCC45 and BABAM1/NBA1 (PubMed:20656690, PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, FAM175A/Abraxas, BRCC3/BRCC36, BRE/BRCC45 and BABAM1/NBA1. In the BRCA1-A complex, interacts directly with FAM175A/Abraxas and BRE/BRCC45 (PubMed:18077395, PubMed:19261748). Component of the BRISC complex, at least composed of FAM175B/ABRO1, BRCC3/BRCC36, BRE/BRCC45 and BABAM1/NBA1 (PubMed:24075985, PubMed:25283148, PubMed:26344097). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985). In the BRISC complex, interacts directly with FAM175B (PubMed:20656690, PubMed:26344097). Identified in a complex with FAM175B and NUMA1 (PubMed:26195665). The BRISC complex interacts with the CSN complex. Component of the BRCA1/BRCA2 containing complex (BRCC), which also contains BRCA1, BRCA2, BARD1, BRE and RAD51. BRCC is a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage. Interacts with BRCA1. Binds polyubiquitin.10 Publications

GO - Molecular functioni

  • polyubiquitin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi122599. 55 interactions.
DIPiDIP-48719N.
IntActiP46736. 26 interactions.
MINTiMINT-1475401.
STRINGi9606.ENSP00000358474.

Structurei

3D structure databases

ProteinModelPortaliP46736.
SMRiP46736. Positions 8-310.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini7 – 148142MPNSequence analysisAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi122 – 13514JAMM motifAdd
BLAST

Sequence similaritiesi

Belongs to the peptidase M67A family. BRCC36 subfamily.Curated
Contains 1 MPN (JAB/Mov34) domain.Curated

Phylogenomic databases

eggNOGiKOG1555. Eukaryota.
COG1310. LUCA.
GeneTreeiENSGT00390000000360.
HOVERGENiHBG002142.
InParanoidiP46736.
KOiK11864.
PhylomeDBiP46736.
TreeFamiTF328524.

Family and domain databases

InterProiIPR000555. JAMM/MPN+_dom.
[Graphical view]
PfamiPF01398. JAB. 1 hit.
[Graphical view]
SMARTiSM00232. JAB_MPN. 1 hit.
[Graphical view]

Sequences (5)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 2 (identifier: P46736-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAVQVVQAVQ AVHLESDAFL VCLNHALSTE KEEVMGLCIG ELNDDTRSDS
60 70 80 90 100
KFAYTGTEMR TVAEKVDAVR IVHIHSVIIL RRSDKRKDRV EISPEQLSAA
110 120 130 140 150
STEAERLAEL TGRPMRVVGW YHSHPHITVW PSHVDVRTQA MYQMMDQGFV
160 170 180 190 200
GLIFSCFIED KNTKTGRVLY TCFQSIQAQK SSESLHGPRD FWSSSQHISI
210 220 230 240 250
EGQKEEERYE RIEIPIHIVP HVTIGKVCLE SAVELPKILC QEEQDAYRRI
260 270 280 290 300
HSLTHLDSVT KIHNGSVFTK NLCSQMSAVS GPLLQWLEDR LEQNQQHLQE
310
LQQEKEELMQ ELSSLE
Length:316
Mass (Da):36,072
Last modified:May 10, 2002 - v2
Checksum:i5720358C1A2F7421
GO
Isoform 1 (identifier: P46736-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     184-208: Missing.

Show »
Length:291
Mass (Da):33,150
Checksum:i56F03D91E313E1D9
GO
Isoform 3 (identifier: P46736-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     46-46: T → TS
     184-208: Missing.

Show »
Length:292
Mass (Da):33,237
Checksum:i70302DC19999753C
GO
Isoform 4 (identifier: P46736-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-114: Missing.

Note: No experimental confirmation available.
Show »
Length:202
Mass (Da):23,458
Checksum:iD6F04C7365A7336D
GO
Isoform 5 (identifier: P46736-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     183-252: ESLHGPRDFWSSSQHISIEGQKEEERYERIEIPIHIVPHVTIGKVCLESAVELPKILCQEEQDAYRRIHS → D

Note: No experimental confirmation available.
Show »
Length:247
Mass (Da):28,027
Checksum:i817A177F34ED1ED8
GO

Sequence cautioni

The sequence AAB29005 differs from that shown. Reason: Erroneous initiation. Curated
The sequence CAO03573 differs from that shown. Reason: Erroneous gene model prediction. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti225 – 2251G → W in AAB29005 (PubMed:8247530).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti74 – 741I → V.
Corresponds to variant rs28997578 [ dbSNP | Ensembl ].
VAR_050097

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 114114Missing in isoform 4. 1 PublicationVSP_037257Add
BLAST
Alternative sequencei46 – 461T → TS in isoform 3. 1 PublicationVSP_037258
Alternative sequencei183 – 25270ESLHG…RRIHS → D in isoform 5. CuratedVSP_037259Add
BLAST
Alternative sequencei184 – 20825Missing in isoform 1 and isoform 3. 2 PublicationsVSP_003261Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X64643 mRNA. Translation: CAA45917.1.
S68015 mRNA. Translation: AAB29005.2. Different initiation.
AY438030 mRNA. Translation: AAR30498.1.
AK298886 mRNA. Translation: BAG60999.1.
AK299194 mRNA. Translation: BAG61237.1.
AK313544 mRNA. Translation: BAG36320.1.
BX293995, BX470111 Genomic DNA. Translation: CAH70537.1.
BX293995, BX470111 Genomic DNA. Translation: CAH70538.1.
BX470111, BX293995 Genomic DNA. Translation: CAI41654.1.
BX470111, BX293995 Genomic DNA. Translation: CAI41655.1.
BX470111 Genomic DNA. Translation: CAO03573.1. Sequence problems.
BX470111 Genomic DNA. Translation: CAO03574.1.
BX470111, BX293995 Genomic DNA. Translation: CAO03575.1.
BX470111, BX293995 Genomic DNA. Translation: CAO03576.1.
BX293995, BX470111 Genomic DNA. Translation: CAO03601.1.
BX293995, BX470111 Genomic DNA. Translation: CAO03602.1.
BC002999 mRNA. Translation: AAH02999.1.
BC006540 mRNA. Translation: AAH06540.1.
CCDSiCCDS56610.1. [P46736-3]
CCDS56611.1. [P46736-1]
CCDS56612.1. [P46736-2]
PIRiI38167.
RefSeqiNP_001018065.1. NM_001018055.2. [P46736-2]
NP_001229569.1. NM_001242640.1. [P46736-3]
NP_077308.1. NM_024332.3. [P46736-1]
UniGeneiHs.558537.

Genome annotation databases

EnsembliENST00000330045; ENSP00000328641; ENSG00000185515. [P46736-2]
ENST00000340647; ENSP00000344103; ENSG00000185515. [P46736-3]
ENST00000369459; ENSP00000358471; ENSG00000185515. [P46736-5]
ENST00000369462; ENSP00000358474; ENSG00000185515. [P46736-1]
GeneIDi79184.
KEGGihsa:79184.
UCSCiuc004fna.4. human. [P46736-1]

Keywords - Coding sequence diversityi

Alternative splicing, Chromosomal rearrangement, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X64643 mRNA. Translation: CAA45917.1.
S68015 mRNA. Translation: AAB29005.2. Different initiation.
AY438030 mRNA. Translation: AAR30498.1.
AK298886 mRNA. Translation: BAG60999.1.
AK299194 mRNA. Translation: BAG61237.1.
AK313544 mRNA. Translation: BAG36320.1.
BX293995, BX470111 Genomic DNA. Translation: CAH70537.1.
BX293995, BX470111 Genomic DNA. Translation: CAH70538.1.
BX470111, BX293995 Genomic DNA. Translation: CAI41654.1.
BX470111, BX293995 Genomic DNA. Translation: CAI41655.1.
BX470111 Genomic DNA. Translation: CAO03573.1. Sequence problems.
BX470111 Genomic DNA. Translation: CAO03574.1.
BX470111, BX293995 Genomic DNA. Translation: CAO03575.1.
BX470111, BX293995 Genomic DNA. Translation: CAO03576.1.
BX293995, BX470111 Genomic DNA. Translation: CAO03601.1.
BX293995, BX470111 Genomic DNA. Translation: CAO03602.1.
BC002999 mRNA. Translation: AAH02999.1.
BC006540 mRNA. Translation: AAH06540.1.
CCDSiCCDS56610.1. [P46736-3]
CCDS56611.1. [P46736-1]
CCDS56612.1. [P46736-2]
PIRiI38167.
RefSeqiNP_001018065.1. NM_001018055.2. [P46736-2]
NP_001229569.1. NM_001242640.1. [P46736-3]
NP_077308.1. NM_024332.3. [P46736-1]
UniGeneiHs.558537.

3D structure databases

ProteinModelPortaliP46736.
SMRiP46736. Positions 8-310.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi122599. 55 interactions.
DIPiDIP-48719N.
IntActiP46736. 26 interactions.
MINTiMINT-1475401.
STRINGi9606.ENSP00000358474.

Protein family/group databases

MEROPSiM67.004.

PTM databases

iPTMnetiP46736.
PhosphoSiteiP46736.

Polymorphism and mutation databases

BioMutaiBRCC3.
DMDMi20532383.

Proteomic databases

EPDiP46736.
MaxQBiP46736.
PaxDbiP46736.
PeptideAtlasiP46736.
PRIDEiP46736.

Protocols and materials databases

DNASUi79184.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000330045; ENSP00000328641; ENSG00000185515. [P46736-2]
ENST00000340647; ENSP00000344103; ENSG00000185515. [P46736-3]
ENST00000369459; ENSP00000358471; ENSG00000185515. [P46736-5]
ENST00000369462; ENSP00000358474; ENSG00000185515. [P46736-1]
GeneIDi79184.
KEGGihsa:79184.
UCSCiuc004fna.4. human. [P46736-1]

Organism-specific databases

CTDi79184.
GeneCardsiBRCC3.
HGNCiHGNC:24185. BRCC3.
HPAiHPA048737.
MalaCardsiBRCC3.
MIMi300617. gene.
neXtProtiNX_P46736.
Orphaneti280679. Moyamoya disease - short stature - facial dysmorphism - hypergonadotropic hypogonadism.
PharmGKBiPA134922847.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1555. Eukaryota.
COG1310. LUCA.
GeneTreeiENSGT00390000000360.
HOVERGENiHBG002142.
InParanoidiP46736.
KOiK11864.
PhylomeDBiP46736.
TreeFamiTF328524.

Enzyme and pathway databases

ReactomeiR-HSA-5693565. Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
R-HSA-5693571. Nonhomologous End-Joining (NHEJ).
R-HSA-5693607. Processing of DNA double-strand break ends.
R-HSA-69473. G2/M DNA damage checkpoint.
SIGNORiP46736.

Miscellaneous databases

ChiTaRSiBRCC3. human.
GeneWikiiBRCC3.
GenomeRNAii79184.
PROiP46736.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000185515.
CleanExiHS_BRCC3.
ExpressionAtlasiP46736. baseline and differential.
GenevisibleiP46736. HS.

Family and domain databases

InterProiIPR000555. JAMM/MPN+_dom.
[Graphical view]
PfamiPF01398. JAB. 1 hit.
[Graphical view]
SMARTiSM00232. JAB_MPN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiBRCC3_HUMAN
AccessioniPrimary (citable) accession number: P46736
Secondary accession number(s): A6QRF8
, A6QRF9, A8MUX5, A8MWH0, A9Z1Y0, A9Z1Y5, B1B062, B4DQN7, Q16107, Q53YX5, Q9BTZ6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: May 10, 2002
Last modified: September 7, 2016
This is version 159 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome X
    Human chromosome X: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Peptidase families
    Classification of peptidase families and list of entries
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.