Henning Wilhelm, Stürzbecher Horst Werner
Institute of Pathology, University Clinic Schleswig-Holstein, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
Toxicology. 2003 Nov 15;193(1-2):91-109. doi: 10.1016/s0300-483x(03)00291-9.
We provide an overview of the functional interrelationship between genes and proteins related to DNA repair by homologous recombination and cell cycle regulation in relation to the progression and therapy resistance of human tumours. To ensure the high-fidelity transmission of genetic information from one generation to the next, cells have evolved mechanisms to monitor genome integrity. Upon DNA damage, cells initiate complex response pathways including cell cycle arrest, activation of genes and gene products involved in DNA repair, and under some circumstances, the triggering of programmed cell death. Deregulation of this co-ordinated response leads to genetic instability and is fundamental to the aetiology of human cancer. Homologous recombination involved in DNA repair is induced by environmental damage as well as misreplication during the normal cell cycle. However, when not regulated properly, it can result in the loss of heterozygocity or genetic rearrangements, central to the process of carcinogenesis. The central step of homologous recombination is the DNA strand exchange reaction catalysed by the eukaryotic Rad51 protein. Here, we describe the recent progress in our understanding of how Rad51 is involved in the signalling and repair of DNA damage and how tumour suppressors, such as p53, ATM, BRCA1, BRCA2, BLM and FANCD2 are linked to Rad51-dependent pathways. An increased knowledge of the role of Rad51 in DNA repair by homologous recombination and its effects on cell cycle progression, tumour development and tumour resistance may provide opportunities for identifying improved diagnostic markers and developing more effective treatments for cancer.
我们概述了与通过同源重组进行DNA修复以及细胞周期调控相关的基因和蛋白质之间的功能相互关系，这些关系与人类肿瘤的进展和治疗抗性有关。为确保遗传信息从一代到下一代的高保真传递，细胞进化出了监测基因组完整性的机制。DNA受损时，细胞会启动复杂的反应途径，包括细胞周期停滞、激活参与DNA修复的基因和基因产物，在某些情况下，还会触发程序性细胞死亡。这种协调反应的失调会导致遗传不稳定，这是人类癌症病因学的基础。参与DNA修复的同源重组由环境损伤以及正常细胞周期中的错误复制诱导。然而，如果调控不当，它可能导致杂合性丧失或基因重排，这是致癌过程的核心。同源重组的核心步骤是由真核Rad51蛋白催化的DNA链交换反应。在这里，我们描述了我们在理解Rad51如何参与DNA损伤的信号传导和修复以及肿瘤抑制因子（如p53、ATM、BRCA1、BRCA2、BLM和FANCD2）如何与Rad51依赖性途径相关联方面的最新进展。对Rad51在同源重组DNA修复中的作用及其对细胞周期进展、肿瘤发展和肿瘤抗性的影响有更多了解，可能为识别改进的诊断标志物和开发更有效的癌症治疗方法提供机会。
