Stürzbecher H W, Donzelmann B, Henning W, Knippschild U, Buchhop S
Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Germany.
EMBO J. 1996 Apr 15;15(8):1992-2002.
The tumour suppressor p53 prevents tumour formation after DNA damage by halting cell cycle progression to allow DNA repair or by inducing apoptotic cell death. Loss of wild-type p53 function renders cells resistant to DNA damage-induced cell cycle arrest and ultimately leads to genomic instabilities including gene amplifications, translocations and aneuploidy. Some of these chromosomal lesions are based on mechanisms that involve recombinatorial events. Here we report that p53 physically interacts with key factors of homologous recombination: the human RAD51 protein and its prokaryotic homologue RecA. In vitro, wild-type p53 inhibits defined biochemical activities of RecA protein, such as three-way DNA strand exchange and single strand DNA-dependent ATPase activity. In vivo, temperature-sensitive p53 forms complexes with RAD51 only in wild-type but not in mutant conformation. These observations suggest that functional wild-type p53 may select directly the appropriate pathway for DNA repair and control the extent and timing of the production of genetic variation via homologous recombination. Gene amplification an other types of chromosome rearrangements involved in tumour progression might occur not only as result of inappropriate cell proliferation but as a direct consequence of a defect in p53-mediated control of homologous recombination processes due to mutations in the p53 gene.
肿瘤抑制因子p53通过阻止细胞周期进程以进行DNA修复或诱导凋亡性细胞死亡，来预防DNA损伤后肿瘤的形成。野生型p53功能的丧失使细胞对DNA损伤诱导的细胞周期停滞产生抗性，并最终导致包括基因扩增、易位和非整倍体在内的基因组不稳定。其中一些染色体损伤基于涉及重组事件的机制。在此，我们报告p53与同源重组的关键因子：人类RAD51蛋白及其原核同源物RecA发生物理相互作用。在体外，野生型p53抑制RecA蛋白的特定生化活性，如三链DNA链交换和单链DNA依赖性ATP酶活性。在体内，温度敏感型p53仅在野生型而非突变构象下与RAD51形成复合物。这些观察结果表明，功能性野生型p53可能直接选择合适的DNA修复途径，并通过同源重组控制遗传变异产生的程度和时间。基因扩增及肿瘤进展中涉及的其他类型染色体重排，可能不仅是不适当细胞增殖的结果，而且是由于p53基因中的突变导致p53介导的同源重组过程控制缺陷的直接后果。
