Mini reviewThe RAD51 gene family, genetic instability and cancer
Introduction
It is well-established that germline mutations in DNA damage-response genes are linked to cancer susceptibility in humans and animal models. Well-characterized human examples of defective DNA repair processes associated with cancer predisposition include DNA mismatch repair (MMR) with colorectal cancer, nucleotide excision repair with skin cancer, and homologous recombination (HR) repair with breast and ovarian cancer [1], [2]. A less well-established, but prevalent, idea is that genetic instability created by sporadic loss of damage-response mechanisms is important in cancer initiation and/or progression. This suggestion has led to much debate over the driving forces involved in cancer development (for contrasting views see: [3], [4], [5]). However, it is not doubted that tumours carry large numbers of genetic alterations (e.g. [6]), and that a succession of genetic changes is usually required to achieve the mature cancer [7]. Therefore, there is considerable interest in the cellular mechanisms that can lead to genetic change, and in particular to genetic instability.
Section snippets
DNA repair by homologous recombination
Several different repair pathways have evolved to cope with DNA damage from both endogenous (e.g. oxidative radicals) and exogenous sources (e.g. radiation, chemicals). Although characterized initially in micro-organisms in the last few years, it has been found that repair of damage by HR is a key pathway in somatic mammalian cells. HR is particularly important during and following DNA replication, when a sister DNA molecule (chromatid) is present as a template for repair. In eukaryotes, the
The RAD51 family: roles in early and late stages of HR?
As noted above, RAD51 itself has the core function of strand invasion: that is, polymerizing onto a 3′ DNA end and mediating the transfer and annealing of the resulting nucleoprotein filament to a complementary homologous strand on the intact chromatid. This invasion displaces the non-complementary intact strand, forming a ‘D-loop’ which enlarges as new DNA synthesis progresses across the break site. Finally, enzymatic resolution of the cross-stranded structure (Holliday junction (HJ)) must
Does the RAD51 family ensure genetic stability?
Early studies, undertaken before the genes were cloned, showed that the frequency of genetic changes was increased in cells lacking XRCC2 and XRCC3 [review: 10], but it is only recently that extensive studies of genetic stability have been published. Knocking out Rad51 in mice gave very early embryonic lethality [34], [35], while knockouts of Xrcc2 [36], Rad51L1 [37], and Rad51L3 [38] allowed the embryos to progress until later but no live births were found. Loss of RAD51 also did not allow
The cancer connection
There are sufficient indications from the above overview to suggest that activities of the RAD51 gene family may influence carcinogenesis, especially in view of the links between RAD51 and the BRCA genes.
To assess the impact of repair gene activity on carcinogenesis, several different approaches have been used. An important source of potential genetic variants is found in naturally occurring polymorphisms in the human genome. The sequencing of repair genes from normal individuals has shown
Conclusions
There is still much to understand about the functions of the RAD51 gene family and the consequences of their mutation or loss. While advances in the characterization of their protein activities are likely to be rapid, other relevant studies will take longer to realize. For example, as yet none of the variant genes has been tested in animal models, especially following treatment with DNA-damaging agents or in association with other gene defects. Having said this, the variant genes that have been
Acknowledgements
The author is supported by the UK Medical Research Council and the European Commission (RISC-RAD contract F16R-CT-2003-508842).
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