mardi 14 août 2012

Mutated genes in cancer (77) – BRCA1


In databases :

Ensembl ( ENSG00000012048
UniProt ( P38398
GeneCards ( BRCA1
HGNC ( 1100 or BRCA1
Enzyme Number (IUBMB): EC 6.3.2

Gene locus:


Protein name:

Breast cancer 1, early onset

Protein Size:

1863 amino acids; about 208 kDa


This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination.
BRCA1 has been implicated in two pathways of DNA double strand break repair: homologous recombination (HR) and non homologous end joining (NHEJ). Upon exposure to DNA damaging agents, BRCA1 becomes hyperphosphorylated and is rapidly relocated, along with Rad51, to sites of DNA synthesis marked by proliferating cell nuclear antigen (PCNA). Rad51, a homolog of the bacterial RecA, is a central player in HR, catalyzing the invasion of the single stranded DNA in a homologous duplex and facilitating the homology search during the establishment of joint molecules. A recent study, however, has indicated that BRCA1 deficient breast cancer cells compensate for this deficiency by upregulating Rad51. The resultant HR may be erroneous and thereby lead to tumorigenesis. In addition, BRCA1 is said to inhibit the MRN complex which is is implicated in bringing together two DNA strands together for the error prone NHEJ. BRCA1-deficient cells are sensitive to ionizing radiation and DNA damaging drugs, such as mitomycin C.

BRCA1 is required for FANCD2 targeting to sites of DNA damage (see Fanconi-associated genes)
Cancer-related alterations:

Cells lacking BRCA1 show defects in DNA repair by homologous recombination.

Defects in BRCA1 are a cause of susceptibility to breast-ovarian cancer familial type 1 (BROVCA1), a condition associated with familial predisposition to cancer of the breast and ovaries (for BROVCA2, see BRCA2; for BROVCA3, see RAD51C). Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as colon and prostate. BRCA1 carries as many as 1000 different disease associated mutations, many of which are rare. These mutations are distributed uniformly along the entire coding region and intronic sequences flanking each exon. Mutations at more than one locus can be involved in different families or even in the same case.  Mutations in BRCA1 are at a high penetrance and are thought to be responsible for more than 80% of inherited breast-ovarian cancer and for 40% of inherited breast cancers.

Defects in BRCA1 are a cause of susceptibility to ovarian cancer. The lifetime risks of ovarian cancer associated with a BRCA1 gene mutation carrier has been estimated as 40 to 50%.

Somatic point mutations (deletions, insertions, substitutions, others) have been observed mostly in breast (2%) and ovarian (2%) tumors. There are no mutation hotspots.

An increased relative risk to the development of cancer of the colon, cervix, uterus, pancreas and prostate has been suggested in BRCA1-mutation carriers.

Specific therapy:

Oral poly(ADP-ribose) polymerase inhibitor olaparib shows activity in patients with advanced breast cancer or recurrent ovarian cancer and BRCA1 or BRCA2 mutations

References (open access):

AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers. Guirouilh-Barbat JK, Wilhelm T, Lopez BS. Oncotarget. 2010 Dec;1(8):691-9.

The role of BRCA1 in DNA damage response. Wu J, Lu LY, Yu X. Protein Cell. 2010 Feb;1(2):117-23.

Poly(ADP-ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic. Yap TA, Sandhu SK, Carden CP, de Bono JS. CA Cancer J Clin. 2011 Jan-Feb;61(1):31-49.

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