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Rad51 recombinase - its role in mitosis and maintenance of genome stability


Double strand breaks in genomic DNA result from environmental insults such as ionizing radiation or chemical damage as well as the normal biological processes of the cell. If left unrepaired, the resulting chromosomal aberrations and gene translocations ca n have deleterious consequences for the cell and ultimately, for the whole organism. Indeed, such genetic instability underlies numerous human diseases, most notably cancer. Accordingly, a network of control mechanisms has evolved to deal with DNA damage m aintaining genetic integrity. One such mechanism is homologous recombination in which damaged DNA is repaired using an undamaged homologous sequence from a sister chromatid as a template. This involves formation of a nucleoprotein complex at the site of th e double strand break mediating DNA strand exchange and repair of the damaged sequence. The conservation of this process from bacteria to mammals attests to its key physiological importance. Rad51, the eukaryotic homologue of the E.coli recA recombinase, i s an integral component of homologous recombination. Following genotoxic insult, Rad51 monomers translocate to sites of DNA damage forming an oligomeric nucleoprotein complex at the site of damage, culminating in repair of such damage. Rad51 has been shown to interact with a range of other DNA repair proteins, which may be necessary for full activity of the recombinase in vivo. The importance of Rad51 is evident by very early embryonic lethality observed in the murine Rad51 knockout, as well as recombinatio n defects and radiosensitivity manifest in the yeast Rad51 mutant. Similarly, conditionally null Rad51~'~ DT40 cells, upon repression of the conditional transgene, accumulate chromosomal abnormalities, arrest in mitosis and subsequently die. The current pr oposal will extensively characterise the role of Rad51 in mitosis as well as its interactions with other proteins of the DNA repair pathway with a view to #

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