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BRCA1

Monday 29 September 2003

Wikipedia

Definition: BRCA1 is a tumor suppressor that functions in controlling cell growth and maintaining genomic stability. The breast and ovarian cancer susceptibility gene BRCA1 encodes a zinc-finger protein of unknown function.

BRCA1 is a tumour suppressor that has important roles in the protection against genomic instability.

Cells lacking BRCA1 are hypersensitive to many DNA-damaging agents such as ultraviolet light and ionizing radiation, and show defects in both S- and G2/M-checkpoint activation following exposure to ionizing radiation.

BRCA1 is a target for both ataxia telangiectasia mutated (ATM)- and ataxia telangiectasia and Rad3 related (ATR)-mediated phosphorylation.

BRCA1 can interact with numerous proteins through its many protein–protein interaction domains.

Interestingly, BRCA1 interacts under normal conditions with the elongating form of RNA polymerase II, but following genotoxic insult BRCA1 becomes phosphorylated and dissociates from the transcription complex.

So, BRCA1 and associated DNA-damage surveillance factors might be associated with the elongating form of RNA polymerase II and might monitor the elongation success of the RNA polymerase.

When transcription halts at a lesion or is disrupted in some other way, BRCA1 and associated factors might relocate to recruit DNA-repair enzymes and to activate cell-cycle checkpoints.

Functions

- BRCA1, as BRCA2, contributes to homologous recombination and DNA repair, to embryonic proliferation, to transcriptional regulation and, for BRCA1, to ubiquitination. BRCA1 is a tumour suppressor that has important roles in the protection against genomic instability.

- homologous recombination and DNA repair

BRCA1 plays essential roles in homologous recombinational repair, non-homologous end joining, and nucleotide excision repair. BRCA1 mediates these functions by interaction with components of the DNA repair machinery and by regulating expression of genes that are involved in these DNA damage repair pathways.

- ubiquitination

BRCA1 associates with BARD1 to form a RING/RING heterodimer. The BRCA1/BARD1 RING complex functions as an ubiquitin (Ub) ligase with activity substantially greater than individual BRCA1 or BARD1 subunits.

The BRCA1 tumor suppressor forms a heterodimer with the BARD1 protein, and the resulting complex functions as an E3 ubiquitin ligase that catalyzes the synthesis of polyubiquitin chains.

UbcH5c and UbcH7 also interact with the BRCA1/BARD1 complex with similar affinity. Although the in vivo substrate(s) is not yet known, BRCA1 has been observed to undergo autoubiquitination and is capable of monoubiquitinating histones 2A and 2AX in vitro.

- telomere maintenance, telomere lengthening and increased anaphase bridge formation

BRCA1 has also been implicated in telomere maintenance through its ability to regulate the transcription of hTERT, the catalytic subunit of telomerase, resulting in telomere shortening, and to colocalize with the telomere-binding protein TRF1.

The high incidence of nonreciprocal translocations in tumors arising from BRCA1 mutation carriers and Brca1-null mice also raises the possibility that BRCA1 plays a role in telomere protection.

BRCA1 function results in telomere lengthening and increased anaphase bridge formation in immortalized cell lines (#16283620#).

BRCA1 could play a role in telomere protection and suggest a potential mechanism for one of the phenotypes of BRCA1-deficient cells (#16283620#).

- BASC complex

BRCA1 is the protein defective in some cases of hereditary breast cancer susceptibility. The recent identification of RECQL3 as part of the BRCA1-associated genome surveillance complex (BASC), links RECQL3 with a number of tumour suppressor and DNA damage repair proteins.

The BASC complex includes MSH2, MHS6, MLH1, ATM, RECQL3, the RAD50-MRE11-NBS1 complex and DNA replication factor C.

Many components of this complex have roles in recognition of DNA damage/unusual DNA structures, suggestive of this complex performing some kind of ’sensor’ role.

To examine the role of RECQL3 within BASC, the subcellular localization of RECQL3 and BRCA1 was analysed before and after exposure to DNA damaging agents. In untreated cells, RECQL3 and BRCA1 colocalization was limited to a few bright nuclear foci.

However, after treatment with hydroxyurea or ionizing radiation, colocalization was greatly enhanced in those cells that were in mid-to-late S phase or in G2.

This could be indicative of specific requirement for BLM/BRCA1 in replication/repair of late replicating DNA.

Consistent with a role for BLM (possibly within BASC) in recognizing abnormal DNA structures, it has been shown that RECQL3 is able to unwind a variety of unusual DNA structures, including G-quadruplex, synthetic X-junctions (models for the Holliday junction), bubbles and forked DNA.

Pathology

- The absence of BRCA1 results in accumulation of chromosome damage, cell cycle abnormalities and apoptosis, leading to developmental abnormalities and adult tumorigenesis.

- Germline mutations in BRCA1 confer high risks of breast and ovarian cancer.

- Mutations in BRCA1 account for at least 80% of families with both breast and ovarian cancer, as well as some non-familial sporadic ovarian cancers. The loss of wild-type BRCA1 in tumours of individuals carrying one nonfunctional BRCA1 allele suggests that BRCA1 encodes a tumour suppressor that may inhibit the proliferation of mammary epithelial cells.

- Cells lacking BRCA1 are hypersensitive to many DNA-damaging agents such as ultraviolet light and ionizing radiation, and show defects in both S- and G2/M-checkpoint activation following exposure to ionizing radiation.

- BRCA1 is a target for both ataxia telangiectasia mutated (ATM)- and ataxia telangiectasia and Rad3 related (ATR)-mediated phosphorylation.

- BRCA1 can interact with numerous proteins through its many protein-protein interaction domains. Interestingly, BRCA1 interacts under normal conditions with the elongating form of RNA polymerase II, but following genotoxic insult BRCA1 becomes phosphorylated and dissociates from the transcription complex.

- So, BRCA1 and associated DNA-damage surveillance factors might be associated with the elongating form of RNA polymerase II and might monitor the elongation success of the RNA polymerase.

- When transcription halts at a lesion or is disrupted in some other way, BRCA1 and associated factors might relocate to recruit DNA-repair enzymes and to activate cell-cycle checkpoints.

Mutations

- germline mutations of BRCA1

  • point mutations
  • BRCA1 gene rearrangements (19%) (#16715518#)

Animal models

- BRCA1-/- knock-out mice (#8563759#)

References

- Prediction of BRCA1 Germline Mutation Status in Women With Ovarian Cancer Using Morphology-based Criteria: Identification of a BRCA1 Ovarian Cancer Phenotype. Fujiwara M, McGuire VA, Felberg A, Sieh W, Whittemore AS, Longacre TA. Am J Surg Pathol. 2012 Aug;36(8):1170-7. PMID: #22790858#

- French JD, Dunn J, Smart CE, Manning N, Brown MA. Disruption of BRCA1 function results in telomere lengthening and increased anaphase bridge formation in immortalized cell lines. Genes Chromosomes Cancer. 2006 Mar;45(3):277-89. PMID: #16283620#

Reviews

- Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. 2004 Sep;4(9):665-76. PMID: #15343273#

- Venkitaraman AR. Tracing the network connecting BRCA and Fanconi anaemia proteins. Nat Rev Cancer. 2004 Apr;4(4):266-76. PMID: #15057286#

- Rosen EM, Fan S, Pestell RG, Goldberg ID. BRCA1 in hormone-responsive cancers. Trends Endocrinol Metab. 2003 Oct;14(8):378-85. PMID: #14516936#

- Hohenstein P, Fodde R. Of mice and (wo)men: genotype-phenotype correlations in BRCA1. Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R271-7. PMID: #12915453#

- Hohenstein P, Giles RH. BRCA1: a scaffold for p53 response? Trends Genet. 2003 Sep;19(9):489-94. PMID: #12957542#

- Monteiro AN. BRCA1: the enigma of tissue-specific tumor development. Trends Genet. 2003 Jun;19(6):312-5. PMID: #12801723#

- Starita LM, Parvin JD. The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair. Curr Opin Cell Biol. 2003 Jun;15(3):345-50. PMID: #12787778#

- Deng CX, Wang RH. Roles of BRCA1 in DNA damage repair: a link between development and cancer. Hum Mol Genet. 2003 Apr 2;12(Suppl 1):R113-23. PMID: #12668603#

- Tutt A, Ashworth A. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med. 2002 Dec;8(12):571-6. PMID: #12470990#

- Futaki M, Liu JM. Chromosomal breakage syndromes and the BRCA1 genome surveillance complex. Trends Mol Med. 2001 Dec;7(12):560-5. Trends Mol Med 2002 Jan;8(1):49. PMID: #11733219#

- Deng CX, Scott F. Role of the tumor suppressor gene Brca1 in genetic stability and mammary gland tumor formation. Oncogene. 2000 Feb 21;19(8):1059-64. PMID: #10713690#

- Welcsh PL, King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet. 2001 Apr ;10(7):705-13. PMID : #11257103#

- Brodie SG, Deng CX. BRCA1-associated tumorigenesis: what have we learned from knockout mice? Trends Genet. 2001 Oct;17(10):S18-22. PMID: #11585672#

- Welcsh PL, Owens KN, King MC. Insights into the functions of BRCA1 and BRCA2. Trends Genet. 2000 Feb;16(2):69-74. PMID: #10652533#

- Stratton MR. Recent advances in understanding of genetic susceptibility to breast cancer. Hum Mol Genet. 1996;5 Spec No:1515-9. PMID: #8875258#

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