Patel K J, Yu V P, Lee H, Corcoran A, Thistlethwaite F C, Evans M J, Colledge W H, Friedman L S, Ponder B A, Venkitaraman A R
Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.
Mol Cell. 1998 Feb;1(3):347-57. doi: 10.1016/s1097-2765(00)80035-0.
Abnormalities precipitated by a targeted truncation in the murine gene Brca2 define its involvement in DNA repair. In culture, cells harboring truncated Brca2 exhibit a proliferative impediment that worsens with successive passages. Arrest in the G1 and G2/M phases is accompanied by elevated p53 and p21 expression. Increased sensitivity to genotoxic agents, particularly ultraviolet light and methylmethanesulfonate, shows that Brca2 function is essential for the ability to survive DNA damage. But checkpoint activation and apoptotic mechanisms are largely unaffected, thereby implicating Brca2 in repair. This is substantiated by the spontaneous accumulation of chromosomal abnormalities, including breaks and aberrant chromatid exchanges. These findings define a function of Brca2 in DNA repair, whose loss precipitates replicative failure, mutagen sensitivity, and genetic instability reminiscent of Bloom syndrome and Fanconi anemia.
小鼠基因Brca2的靶向截短所引发的异常情况表明其参与了DNA修复过程。在培养过程中，携带截短型Brca2的细胞表现出增殖障碍，且随着传代次数的增加而加剧。细胞在G1期和G2/M期停滞伴随着p53和p21表达的升高。对基因毒性剂，尤其是紫外线和甲基磺酸甲酯的敏感性增加，表明Brca2功能对于DNA损伤后的生存能力至关重要。但检查点激活和凋亡机制在很大程度上未受影响，从而表明Brca2参与修复过程。这一点通过染色体异常的自发积累得到证实，包括断裂和异常染色单体交换。这些发现确定了Brca2在DNA修复中的功能，其缺失会导致复制失败、诱变敏感性和遗传不稳定性，这与布卢姆综合征和范可尼贫血相似。
