Arnold Katrin, Kim Min-Kyoung, Frerk Katrin, Edler Lutz, Savelyeva Larissa, Schmezer Peter, Wiedemeyer Ruprecht
Department of Tumour Genetics B030, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Cancer Lett. 2006 Nov 8;243(1):90-100. doi: 10.1016/j.canlet.2005.11.041. Epub 2006 Jan 31.
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.
BRCA2蛋白通过在DNA双链断裂的同源重组修复中发挥关键作用，参与维持基因组稳定性。BRCA2的双等位基因失活会导致DNA修复缺陷，并与染色体不稳定表型相关。最近对家族性乳腺癌聚集区的研究表明，杂合BRCA2突变携带者中也存在染色体重排和更高的姐妹染色单体交换率。在本研究中，比较了杂合BRCA2突变携带者和野生型亲属的淋巴母细胞系在BRCA2 mRNA和蛋白表达以及修复γ射线和丝裂霉素C诱导的DNA损伤能力方面的差异。与BRCA2+/+细胞相比，BRCA2+/-细胞中全长BRCA2蛋白的含量较低。γ-H2AX蛋白水平的动力学显示BRCA2+/-细胞在DNA双链断裂修复方面存在明显缺陷。这些结果表明BRCA2+/-细胞存在单倍剂量不足表型，提示BRCA2+/-携带者中功能性BRCA2蛋白数量的减少不足以有效修复DNA双链断裂，这种情况可能导致基因组稳定性受损。
