Lower level of BRCA2 protein in heterozygous mutation carriers is correlated with an increase in DNA double strand breaks and an impaired DSB repair.

The BRCA2 protein is involved in the maintenance of genomic stability through its key role in homologous recombination repair of DNA double strand breaks. Biallelic inactivation of BRCA2 leads to a defect in DNA repair and is associated with a chromosomal instability phenotype. Recent studies on familial breast cancer clusters revealed chromosomal rearrangements and higher rates of sister chromatid exchanges also in heterozygous BRCA2 mutation carriers. In the present study, lymphoblastoid cell lines of heterozygous BRCA2 mutation carriers and of wildtype relatives were compared with regard to BRCA2 mRNA and protein expression and capacity to repair DNA damage induced by gamma-irradiation and mitomycin C. BRCA2+/- cells showed lower amounts of the full-length BRCA2 protein compared to BRCA2+/+ cells. The kinetics of gamma-H2AX protein level revealed distinct defects in DNA double strand break repair in the BRCA2+/- cells. These results are indicative of a haploinsufficiency phenotype in BRCA2+/- cells, suggesting that reduced amounts of functional BRCA2 protein in BRCA2+/- carriers are insufficient for an efficient repair of DNA double strand breaks, a condition that could contribute to the impairment of genomic stability.