Homologous recombination and cell cycle checkpoints: Rad51 in tumour progression and therapy resistance.

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.

p53 interacts with hRAD51 and hRAD54, and directly modulates homologous recombination.

p53 inhibits tumorigenesis through a variety of functions, including mediation of cell cycle arrest, premature senescence, and apoptosis.p53 also can associate with several DNA helicases and proteins involved in homologous recombination. In this study, we show that p53, hRAD51, and hRAD54 coimmunoprecipitated and colocalized with each other at endogenous levels in normal cells. Colocalization was observed with the phosphoserine-15 form of p53 at presumed DNA processing sites after the induction of DNA breaks. hRAD54 bound directly to the p53 COOH terminus in vitro without a nucleic acid intermediate. We then investigated the functional consequences of these protein interactions. A host cell reactivation assay revealed that the elevation in recombination observed after p53 inactivation is dependent on the hRAD51 pathway and that p53-dependent antirecombinogenic activity can be attributed to p53 binding to hRAD51 directly. These data support the hypothesis that p53 helps maintain genetic stability through transcription-independent modulation of homologous recombination factors.