BRCA2: Breast Cancer Susceptibility Gene 2

Lindy BehrendMarch 4, 2003

Breast Cancer

• 2nd major cause of cancer death in women

• 1 in 8 women likely to develop breast cancer

• 5-10% hereditary: of these, 1/3 due to mutations in BRCA1, 1/3 due to mutations in BRCA2, and 1/3 due to mutations in other unknown/unidentified genes

Risk Factors

• exposure to chemicals• high dose radiation• other environmental

exposures• smoking and drinking• childless• first child after 30

BRCA2

• Inherited mutations in BRCA2 can increase breast cancer risk by 90% and ovarian cancer risk by 15-20%

• Increased chance of developing these cancers at a young age

• Increased risk of lymphoma, melanoma, and cancers of the colon, pancreas, gall bladder, bile duct and stomach

BRCA2

• Located on chromosome 13

• A tumor suppressor gene

• Inherited in an autosomal dominant fashion

BRCA2

• Interacts with RPA and RAD51 during homologous recombination to repair double-strand DNA breaks caused by ionizing radiation and DNA cross-linking

BRCA2 function determined by looking at its structure

• C-terminal region: highly conserved amino acid sequence often mutated in mouse, rat, and human tumors

• Contains 3 oligonucleotide binding folds that are present in most single-strand DNA-binding proteins

• Interact with DNA in same way as RPA

BRCA2 function determined by looking at its structure

• Tower domain: homologous to DNA-binding domains of bacterial recombinases that bind double stranded DNA

• 4 of 7 most common missense mutations in BRCA2 occur here

BRCA2 stimulates RAD51-mediated recombination

• During S phase, BRCA1, BRCA2, and RAD51 colocalize in nuclear dots and then disperse after the arrest of synthesis

• In response to ionizing radiation or cross-linked DNA, these nuclear dots reform smaller foci

• Mice lacking one of these three genes show proliferation defects and die in utero

• In vitro assays indicate strand pairing and exchange are strongly dependent on RPA

• BRCA2 not found to be a successful substitute for RPA

• Adding BRCA2 stimulates the reaction in proportion to the amount added

Homologous Recombination

• RPA coats strands• RAD 51 binds, initiates

recombination• RAD52, RAD54-RAD57

are mediator proteins to keep RPA from binding so tightly it interferes with RAD51

• BRCA2 stimulates strand transfer

Remaining Uncertainties

• What is the mechanism by which BRCA2 interacts with RAD51?

• Why are there no BRCA2 homologs in yeast, flies, or worms?

• Why do mutations in BRCA2 produce tumors in select tissues?