DNA damage is a common occurrence that compromises the functional integrity of our genome. Well over 10,000 instances of DNA damage are estimated to occur daily in every human cell. The causative agents of the damage are mainly free radicals that are produced as natural by-products of food metabolism. If damaged DNA is left unrepaired, it generates mutations, replication errors, persistent DNA damage and genomic instability, which are ultimately associated with cancer and ageing. The mechanisms of DNA repair at a molecular level are largely unknown and a better understanding of the detailed mechanisms and principles underlying damage recognition in prokaryotes is an essential step towards obtaining a complete overview of the more complex human DNA repair systems. In prokaryotes, four repair pathways exist (homologous recombination, base-excision repair, nucleotide-excision repair and mismatch repair), all of which are essential for viability.

Homologous recombination, in addition to its fundamental role in genetic diversification of bacterial genomes, plays a key role in the repair of a variety of DNA lesions, including the lethal double-strand breaks. Initiation of homologous recombination can be carried out by either the RecBCD or the RecFOR proteins; in both cases these proteins act as mediators for RecA binding to single-stranded DNA in order to allow for homologous strand invasion. Genome sequence analysis of Deinococcus radiodurans, an outstanding bacterium capable of repairing and recovering from several hundred DNA double-strand breaks in its genome, has revealed that the genes encoding RecB and RecC proteins are missing, while all the genes encoding members of the RecFOR pathway (RecQ, RecJ, RecO, RecF and RecR) are present [1]. Inhibition of the RecFOR pathway in D. radiodurans increases the sensitivity of D. radiodurans cells to gamma-radiation, suggesting that RecFOR is essential for the repair of double-strand breaks.

 

Fig. 74: Crystal structure of the hetero-hexameric complex formed between RecO (blue) and RecR (bronze). Zn2+ ions are illustrated as green spheres.


An increasing amount of structural information is becoming available for these proteins, which together with the biochemical and genetic data will no doubt improve our current understanding of the initial steps in homologous recombination. The individual crystal structures of RecF, RecO [2] and RecR from D. radiodurans have been solved over the past three years allowing the mapping of regions involved in protein-protein and protein-DNA interdeng of regamaged DNA ia propel=aEcoveegamaged th" wiwhich toge mappdaiione/span>tentringuble-e in homologous rec class="HLills> Crystalan class="HLintextref">[2] estimat Crysta <>Fig. 74:

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