The survival of species is guaranteed by maintenance of genome stability, specifically the protection of DNA integrity. DNA is a chemically reactive molecule, which is continuously threatened by DNA-damaging agents, both exogenous (environmental, including ionizing radiation and mutagenic chemicals) and endogenous (byproducts of cellular metabolism, such as oxygen radicals). The continuous onslaught by such physical and chemical agents result in about 100,000 modifications per cell per day [1], and this calls for the existence of diverse DNA repair systems within the cell. The many different types of lesions that can occur in DNA have necessitated the evolution of multiple pathways to repair specific subsets of lesions. Therefore, an intricate web of repair pathways counteracts damage to free DNA from modifications that would lead to mutations, thus ensuring its error-free transcription and replication. The lethal effects of ionizing radiation have been attributed to the formation of DNA double-strand breaks (DSBs), which, if misrepaired, can lead to chromosomal aberrations including rearrangements, deletions and translocations, cell death and, in higher organisms, cancer (see Chapter 6). Because unrepaired DSBs result in genomic fragmentation, it is of critical importance that the DSBs are repaired precisely and in a timely fashion. Homologous recombination is a high fidelity pathway that ensures the accurate repair of the broken DNA by using the information present on the undamaged template DNA, usually the sister chromatid. The process is carried out by the conserved RAD52 epistasis group proteins, identified by the genetic analyses of ionizing radiation sensitive Saccharomyces cerevisiae mutants [1, 2]. In mammals, this group includes the MRN (RAD50/MRE11/NBS1) complex, RAD51, the RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3), RAD54 and RAD54B [3]. In addition, mammalian homologous recombination is also modulated by the products of the breast cancer susceptibility genes, BRCA1 and BRCA2 [4], and perhaps also genes involved in Fanconi anemia.

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Kanaar, Prof. Dr. R. (promotor), Hoeijmakers, Prof. Dr. J.H.J. (promotor), Dutch Cancer Society (KWF)
J.H.J. Hoeijmakers (Jan) , R. Kanaar (Roland)
Erasmus University Rotterdam
hdl.handle.net/1765/11971
Erasmus MC: University Medical Center Rotterdam

Agarwal, S. (2008, April 2). The Cell Biology of Rad54: Implications for homologous recombination. Retrieved from http://hdl.handle.net/1765/11971