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FLASH GENE

Symbol

BRCA1

contributors: mct/shn - updated : 03-06-2020

HGNC name	breast cancer 1, early onset
HGNC id	1100

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic thymus       highly Nervous brain hindbrain cerebellum   highly Homo sapiens   brain limbic system hippocampus dentate gyrus highly Homo sapiens Reproductive female system ovary         female system breast         male system testis     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular     Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol   epithelial cell

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	high levels of BRCA1 expression have been found in the embryonic neuroectoderm

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a N terminal RING zinc finger domain, and N-terminus of BRCA1 harbors a degron sequence that is sufficient and necessary for conferring BRCA1 degradation
	a sequence homology in the C terminal part, with the putative consensus sequence of granin family
	two BRCT adaptor domains BRCTN and BRCTC, BRCA C terminus (BRCT) motifs that form a phosphoprotein recognition domain, and BRCT phosphoprotein recognition, but not the E3 ligase activity, is required for BRCA1 tumor suppression
	a tandem repeat of the BRCT domain (BRCT-tan), playing a critical role in BRCA1-mediated tumour suppression, and are phospho-serine/threonine recognition modules essential for the function of BRCA1
	an N-terminal nuclear export sequence (NES)
	a C-terminal fragment that is unstable in cells as it is targeted for degradation by the N-end rule pathway, and is stable in cells lacking ATE1, a component of the N-end rule pathway
	a gamma-tubulin-binding domain

conjugated

PhosphoP

HOMOLOGY

interspecies	ortholog to Brca1, Rattus norvegicus
	ortholog to Brca1, Mus musculus
	ortholog to BRCA1, Pan troglodytes

Homologene

FAMILY

CATEGORY

regulatory , transcription factor , tumor suppressor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
	intracellular,nucleus,chromatin/chromosome
text	nucleus in normal cells, intranuclear foci formation induced by interaction with BARD1
	N terminus and C-terminal BRCT domains is sufficient to mediate effective BRCA1 targeting to the centrosome
	BCL2 and BRCA1 colocalized to mitochondria and endoplasmic reticulum in a process requiring the TM domain of BCL2

basic FUNCTION	involved in the dynamics of the mitotic spindle and in the segregation of duplicated chromosomes
	negative regulator of mammary cell growth (in a RB-dependent fashion)
	activating DNA repair through homologous recombination, in cooperation with BRCA2, RAD51 and RAD52, P-BRCA
	playing a significant role by its ubiquitin ligase activity in tumour suppression
	regulating the G2/M checkpoint by activating CHEK1 upon DNA damage
	complexing with RNA polymerase II holoenzyme and involved in the regulation of hol-pol function
	recruiting CREBBP/EP300 and interacting with components of the histone deacetylase complex in cooperation with STAT1
	mediating ubiquitin-conjugating enzyme (E2)-dependent ubiquitination through the RING finger domain (ubiquitin protein ligase activity)
	induction of BRCA1 triggers JNK/SAPK (MAPK8) dependent apoptosis through induction of DDIT1 (GADD45)
	transcriptional control through modulation of chromatin structure
	having critical function in the proliferation and differentiation of neural progenitor cells
	is required for the proliferative effects of EZH2
	required for appropriate cell cycle arrests after ionizing irradiation
	involved in transcriptional regulation of P21 in response to DNA damage
	exerts transcriptional repression through interaction with RBBP8 in the C-terminal BRCT domain and ZNF350 in the central domain)
	involved in regulation of lipid biosynthesis through its inhibition of ACACA activity, which could be a novel tumor suppressor function of BRCA1
	required for FANCD2 targeting to sites of DNA damage
	inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation
	recruited to the telomere in a Rad50-dependent manner and may regulate telomere length and stability, in part through its presence at the telomere
	UIMC1/BRCA1 complex, is required for efficient BRCA1 focal recruitment, and suppress excessive DSB (DNA double-strand breaks) end processing, homologous recombination-type DSB repair, and overt chromosomal instability
	function of BRCA1 in the control of centriole pairing
	required for postreplication repair after UV-induced DNA damage
	role of BRCA1 in maintaining global heterochromatin integrity accounts for many of its tumour suppressor functions
	BRCA1 and its ubiquitin E3 ligase activity are required for gene silencing in constitutive heterochromatin
	ubiquitin ligase activity of BRCA1 is essential for the maintenance of the ubiquityl-histone H2A mark within constitutive heterochromatic regionsin human cells derived from breast cancers
	multifunctional protein that also ubiquitinates TUBG1 and, consequently, inhibits microtubule nucleation at the centrosome
	epigenetically represses MIR155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the MIR155 promoter
	BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers
	functions independently of homologous recombination in DNA interstrand crosslink repair
	novel functions of BRCA1 in miRNA biogenesis, which may be linked to its tumor suppressor mechanism and maintenance of genomic stability
	tripartite regulation of homologous recombination by RNF8, BRCA1, and TP53BP1
	nuclear tumor suppressor that is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR)
	BRCA1 and HSP90AA1 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation
	plays a protective role in heat toxicity and thermal stress induces BRCA1 degradation
	role of BRCA1 in regulating damage-associated checkpoint and repair responses to HSP90AA1 inhibitors
	RNF168 is important for HR deficiency in cells with BRCA1 silencing
	BRCA1 E3 ligase activity regulates the G2/M cell cycle checkpoint and, thus, contributes to maintenance of genomic stability
	BRCA1 and TP53BP1 play decisive roles in the choice of DNA double-strand break repair mechanisms
	OLA1 plays an important role in centrosome regulation together with BRCA1
	BRCA1, FANCD2 and CHEK1 are potential targets for the modulation of radiation response in bystander cells
	during mitosis, BRCA1 and its positive regulator CHEK2 are localized at centrosomes and are required for the regulation of microtubule plus end assembly, thereby ensuring faithful mitosis and numerical chromosome stability
	BRCA1 and BARD1 might have common as well as separate functions
	BRCA1 accumulation at DNA damage sites is an important step for its function in the DNA damage response and in DNA repair
	FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2, are required for mitophagy
	competes with TP53BP1 early in the repair process to promote HR and restrict error-prone NHEJ
	likely BRCA1/FANCS may play several distinct roles during the process of DNA interstrand crosslink (ICL) repair
	complex BRCA1-BARD1 functions in the repair of DNA double-stranded breaks by homologous recombination
	late role of BRCA1-BARD1 in homologous recombination, an attribute of the tumour suppressor complex that could be targeted in cancer therapy
	BRCA1 is a POU2F1 ubiquitin ligase that catalyzes POU2F1 degradation to promote oxidative metabolism and restrict tumorigenicity
	BRCA1-BARD1 functions in DNA repair, replication fork maintenance and tumour suppression
	function of BARD1 in centrosome regulation in cooperation with BRCA1/OLA1/RACK1
	BRCA1-BARD1 complex directs the DNA double-strand break (DSB) repair pathway choice to error-free homologous recombination (HR) during the S-G2 stages

CELLULAR PROCESS	cell cycle
	cell life, cell death/apoptosis
	nucleotide, repair
	nucleotide, genomic integrity
	nucleotide, transcription
	protein, ubiquitin dependent proteolysis

PHYSIOLOGICAL PROCESS

development

text	regulator of gene stability (caretaker)

PATHWAY

metabolism

lipid/lipoprotein

signaling

chromosome instability pathway

a component	heterodimer with BARD1 containing a ubiquitin ligase activity that is important for prevention of breast and ovarian cancer and inducing the formation of conjugated ubiquitin structures during DNA replication and repair
	BRCA1, CCDC98 and UIMC1 form a functional complex and participate in the DNA damage response
	BRCA1/BARD1 may promote genome stability and tumor suppression through its involvement in other cellular processes, such as mitotic spindle assembly and cell cycle checkpoint control
	BRCA1/E2F1/RBBP8 binding to ATM promoter activates ATM transcription
	OLA1 is a part of the BRCA1/BARD1/gamma-tubulin complex that is critically involved in centrosome amplification and microtubule aster formation

INTERACTION

DNA	promoter regions of CYP1A1 and CYP1B1
	inactive X chromosome

RNA

XIST RNA

small molecule	metal binding,
	Zn2+ binding

protein	importin-alpha subunit of the nuclear transport signal receptor
	Rad51
	p32 and p65 BRCA1 interacting proteins, cyclin A, cyclin B1, cyclin D1, cdc2, cdk2 and E2F
	BRAP2
	BAP1
	p53
	a component of the RNA polymerase II (Pol II) holoenzyme
	BRCA2
	c-Myc
	CtIP
	gamma-tubulin
	CtBP
	RbAp46 and RbAp48, HDAC1 and HDAC2
	hRad50-hMre11-p95 complex
	hypophosphorylated form of pRb
	CBP/p300
	BRCA1-associated genome surveillance complex: MSH2, MSH6, MLH1, ATM, BLM, and the RAD50-MRE11-NBS1 protein complex, and DNA replication factor C, RFC
	RNA polymerase II
	STAT1
	valosin-containing protein, VCP
	ZBRK1
	ATF1
	androgen receptor, AR and p160
	checkpoint kinase ATR
	JAK1 and JAK2
	FANCD2
	BACH1
	retinoblastoma suppressor (Rb)-associated protein 46, RbAp46
	c-Fos oncogene regulator Elk-1
	LMO4
	GADD45
	N-Myc-interacting protein, Nmi
	c-Abl
	JUNB and JUND
	alpha- and beta-tubulin
	Fanconi anemia protein, FANCA
	Acetyl Coenzyme A (CoA) Carboxylase alpha, ACCA
	ER-alpha
	Stat5a
	phosphatase 1alpha, PP1alpha
	Sp1
	p65/RelA
	four and a half LIM-only protein 2, FHL2
	BARD1/BRCC45/BRCC36
	IFI16
	p53
	Aurora-A
	FHL2
	zinc-finger-containing protein NUFIP
	nucleolar phosphoprotein nucleophosmin/B23, NPM
	SWI/SNF enzymes
	mitogen-activated protein kinase (MAPK) kinase kinase 3, MEKK3
	TRAP220
	Cdk-activating kinase, CAK
	Smad3
	hGCN5, TRRAP, and hMSH2/6
	poly(A)-binding protein 1, PABP
	cyclin D1
	Abraxas and RAP80
	TR-interacting protein, ATRIP
	CCDC98
	aryl hydrocarbon receptor, AhR
	ERK1/2
	p14ARF
	Ku80
	vitamin D receptor, VDR
	Rap80
	NBA1
	Mediator of Rap80 Interactions and Targeting 40 kd, MERIT40
	PALB2
	NINL (
	centrosomal protein Nlp
	E2s
	deleted in breast cancer 1, DBC1/KIAA1967
	FANCJ
	BRD7
	MRG15
	UBXN1
	HERC2
	UE2I
	TFII-I
	BCL2
	KIAA0101
	YY1 binds to the promoter of BRCA1, and its overexpression resulted in increased expression of BRCA1 and a number of BRCA1 downstream genes
	Cockayne syndrome B, CSB
	BARD1
	AP2-alpha, PAX2 and ZF5
	CDK1
	interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation
	gamma tubulin, CRM1, and Aurora A
	BRCA1 antagonises TP53BP1-dependent DNA repair in S phase by inhibiting its interaction with chromatin proximal to damage sites
	claspin (
	loss of HSP90AA1 function abolishes BRCA1-dependent DSB repair
	SKP1 regulates BRCA1 protein stability
	FBXO44 is an important protein that influences BRCA1 protein level
	BRCA1 heterodimerizes with its partner protein, BARD1, via the RING domain present in both proteins
	BRCA1-dependent degradation of cyclin B and CDC25C is reversed by proteasome inhibitors and is enhanced following DNA damage, which may represent a possible mechanism to prevent cyclin B and CDC25C accumulation, a requirement for mitotic entry
	RBBP8 interacts with NBN and BRCA1, and connects CDK and ATM to regulate homologous recombination (HR)-mediated double-strand break repair
	ZNF423 appeared to be an estrogen-inducible BRCA1 transcription factor
	DCLRE1B is a nuclease required for efficient localization of the DNA repair proteins, FANCD2 and BRCA1
	BRCA1 downregulates the kinase activity of PLK1 by modulating the dynamic interactions of AURKA, BORA, and PLK1
	TP53BP1 recruitment requires the direct recognition of a DSB-specific histone code and its influence on pathway choice is mediated by mutual antagonism with BRCA1
	KDM5B is required for efficient DSB repair and for the recruitment of XRCC6 and BRCA1, the essential component of nonhomologous end-joining and homologous recombination, respectively
	FAM175A is a BRCA1 BRCT domain-interacting protein, playing a role in tumor suppression
	BRCA1 and BLM interact with RAD50 predominantly in S- and G2-phases, respectively
	functions as a bona fide tumor suppressor by regulating the protein stability and function of BRCA1 in breast cancer
	BRCA1 and BRIP1 cooperatively promote interstrand crosslinker induced centrosome amplification through the activation of PLK1
	gain of function mutant TP53 proteins cooperate with E2F4 to transcriptionally downregulate RAD17 and BRCA1 gene expression
	CEP72 is a novel BRCA1-interacting protein
	high levels of CEP72 counteract CHEK2 as a positive regulator of BRCA1 to ensure proper mitotic microtubule assembly
	BABAM1 is an essential component of the RAP80 ubiquitin recognition complex that targets BRCA1 to DNA damage sites
	mitotic function of BRCA1 depends on its phosphorylation by the tumor-suppressor kinase CHEK2 and this regulation is required to ensure normal microtubule plus end assembly rates within mitotic spindles
	dual molecular mechanism by which the CHEK2-BRCA1 axis restrains oncogenic AURKA activity during mitosis and BRCA1 itself is a target for AURKA relevant for chromosomal instability (CIN)
	ERCC5 is a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR)
	in cells, USP51 is recruited to chromatin after DNA damage and regulates the dynamic assembly/disassembly of TP53BP1 and BRCA1 foci
	BRCA1 (FANCS), MDC1, and RNF8 are required for BRCA2 (FANCD1) and SLX4 (FANCP) accumulation on the sex chromosomes during meiosis
	ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair
	ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment
	both BRCA1 and BARD1 bind DNA and interact with RAD51, and BRCA1-BARD1 enhances the recombinase activity of RAD51
	BRCA1 promotes oxidative metabolism by degrading POU2F1, a transcription factor with proglycolytic and tumorigenic effects
	regulation of BRCA1-BARD1 heterodimerization through SIRT2 deacetylation, elucidating a critical upstream signaling event directing BRCA1-BARD1 heterodimerization, which facilitates HR and tumor suppression
	novel function of the BRCA1-BARD1 complex in the regulation of TOP2B and Pol II-mediated gene expression

cell & other	SWI/SNF chromatin remodeling complex through SMARCA4
	associated with the centrosome during mitosis

REGULATION

repressed by	LMO4 in association with RBBP8 in breast tissue
		CTBP1 (represses BRCA1 transcription by binding to the E2F4 site of the BRCA1 promoter)
		Brg-1 and ets-2

Phosphorylated by	ataxia telangiectasia mutated protein-related protein kinase, ATR
	CDK2-cyclin A or E
	casein kinase 2, CK2
	heregulin
	regulated by Cds1 kinase (hCds1/Chk2)

Other	nuclear cell cycle regulated phosphoprotein of breast epithelium
	phosphorylated by ATM protein kinase in response to ionizing radiation induced DNA damage,regulating the expression of GADD45s and CDLN1A
	potentiated by binding JUNB to one of the transactivation domain of BRCA1
	CAV1 enhances BRCA1 protein and mRNA levels
	regulated by UBXN1 (regulates the enzymatic function of BRCA1 in a manner that is dependent on its ubiquitination status)
	hypoxia is a driving force for long-term silencing of BRCA1, thereby promoting genome instability and tumor progression
	regulated by Cds1 kinase (hCds1/Chk2)
	methylated by PRMT1
	negatively regulated by SUMO1
	Ubiquitinated and downregulated by ubiquitin-conjugating enzyme E2T

ASSOCIATED DISORDERS

corresponding disease(s)

BRCA1 , FANCS

related resource

Breastcancer

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   or loss of function in breast, ovarian carcinomas (sporadic or not) tumoral germinal mutation       increased risk of Prostate carcinoma in men constitutional     --over   in proliferative cells tumoral germinal mutation     loss of function in patients with primary ovarian, fallopian tube, or peritoneal cancers tumoral       loss of function BRCA1 loss activates CTSL1-mediated degradation of TP53BP1 tumoral       loss of function loss of BRCA1 following HSP90AA1 inhibition is a key upstream event leading to defective DSB repair, failure of G2/M checkpoint activation, and potentiation to DNA damaging agents

Susceptibility

to breast cancer

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     clinically relevant target for enhancing sensitivity in refractory and/or resistant malignancies cancer     MIR155 is a potential therapeutic target for BRCA1-deficient tumors cancer metastases   Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis cancer     is a clinically relevant target for enhancing sensitivity in refractory and/or resistant malignancies

ANIMAL & CELL MODELS

	mice homozygous for the mutant BRCA1 allele died in utero between 10 and 13 days of gestation due to abnormalities in the neural tube, spina bifida and anencephaly
	Brca1+/- mice are normal and fertile and lack tumors by age eleven months, while Brca1-/- mice die before day 7.5 of embryogenesis due to a failure of the proliferative burst
	Brca1-deficient mouse embryonic stem cells have impaired repair of chromosomal DNA double-strand breaks by homologous recombination
	impact of the Brca1 or Brca2 null mutation is less severe in a p53 null background
	mice deficient in the Brca1 exon 11 isoform (Brca1Delta11/Delta11) died late in gestation because of widespread apoptosis
	most female Brca1Delta11/Delta11 Trp53+/- mice develop mammary tumors with loss of the remaining Trp53 allele within 6-12 months
	Brca1(Delta11/Delta11)Gadd45a(-/-) embryos at embryonic days 9.5-10.5 were exencephalic and exhibited a high incidence of apoptosis accompanied by altered levels of BAX, BCL-2, and p53