Godthelp Barbara C, van Buul Paul P W, Jaspers Nicolaas G J, Elghalbzouri-Maghrani Elhaam, van Duijn-Goedhart Annemarie, Arwert Fré, Joenje Hans, Zdzienicka Małgorzata Z
Department of Toxicogenetics, Leiden University Medical Center, Building 2, Postzone S-6-P, 2300 RC, Leiden, The Netherlands.
Mutat Res. 2006 Oct 10;601(1-2):191-201. doi: 10.1016/j.mrfmmm.2006.07.003. Epub 2006 Aug 21.
Fanconi anemia (FA) is an inherited cancer-susceptibility disorder, characterized by genomic instability and hypersensitivity to DNA cross-linking agents. The discovery of biallelic BRCA2 mutations in the FA-D1 complementation group allows for the first time to study the characteristics of primary BRCA2-deficient human cells. FANCD1/BRCA2-deficient fibroblasts appeared hypersensitive to mitomycin C (MMC), slightly sensitive to methyl methane sulfonate (MMS), and like cells derived from other FA complementation groups, not sensitive to X-ray irradiation. However, unlike other FA cells, FA-D1 cells were slightly sensitive to UV irradiation. Despite the observed lack of X-ray sensitivity in cell survival, significant radioresistant DNA synthesis (RDS) was observed in the BRCA2-deficient fibroblasts but also in the FANCA-deficient fibroblasts, suggesting an impaired S-phase checkpoint. FA-D1/BRCA2 cells displayed greatly enhanced levels of spontaneous as well as MMC-induced chromosomal aberrations (CA), similar to cells deficient in homologous recombination (HR) and non-D1 FA cells. In contrast to Brca2-deficient rodent cells, FA-D1/BRCA2 cells showed normal sister chromatid exchange (SCE) levels, both spontaneous as well as after MMC treatment. Hence, these data indicate that human cells with biallelic BRCA2 mutations display typical features of both FA- and HR-deficient cells, which suggests that FANCD1/BRCA2 is part of the integrated FA/BRCA DNA damage response pathway but also controls other functions outside the FA pathway.
范可尼贫血（FA）是一种遗传性癌症易感性疾病，其特征为基因组不稳定以及对DNA交联剂高度敏感。在FA-D1互补组中发现双等位基因BRCA2突变，首次使得对原发性BRCA2缺陷型人类细胞的特征进行研究成为可能。FANCD1/BRCA2缺陷型成纤维细胞对丝裂霉素C（MMC）表现出高度敏感，对甲基磺酸甲酯（MMS）稍有敏感，并且与源自其他FA互补组的细胞一样，对X射线照射不敏感。然而，与其他FA细胞不同，FA-D1细胞对紫外线照射稍有敏感。尽管在细胞存活方面观察到缺乏X射线敏感性，但在BRCA2缺陷型成纤维细胞以及FANCA缺陷型成纤维细胞中均观察到显著的抗辐射DNA合成（RDS），这表明S期检查点受损。FA-D1/BRCA2细胞显示出自发性以及MMC诱导的染色体畸变（CA）水平大幅提高，类似于同源重组（HR）缺陷型细胞和非D1型FA细胞。与Brca2缺陷型啮齿动物细胞不同，FA-D1/BRCA2细胞无论是自发的还是在MMC处理后，均显示出正常的姐妹染色单体交换（SCE）水平。因此，这些数据表明，具有双等位基因BRCA2突变的人类细胞表现出FA缺陷型细胞和HR缺陷型细胞的典型特征，这表明FANCD1/BRCA2是FA/BRCA DNA损伤反应综合途径的一部分，但也控制FA途径之外的其他功能。
