Mechanism of homologous recombination: mediators and helicases take on regulatory functions

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Abstract
Homologous recombination (HR) has an important role in DNA repair, DNA replication, meiotic chromosome segregation and telomere maintenance. HR is tightly regulated by DNA helicases. A defect in, or deregulation of, HR can lead to cell-cycle arrest, genome destabilization and cancer formation. DNA double-stranded breaks (DSBs) that are caused by exposure to ionizing radiation and other DNA-damaging agents are strong inducers of HR. Programmed HR processes such as meiotic recombination and yeast mating-type switching are initiated through DSB formation. Several HR pathways that are initiated by DSBs have been elucidated. In the DNA double-strand-break repair (DSBR) pathway, a DNA intermediate that contains two Holliday junctions is made. Resolution of this DNA intermediate can produce crossover recombinants that harbour a reciprocal exchange of the arms of the recombining chromosomes. Crossovers are crucial for chromosome segregation at meiosis I, but their formation is suppressed in mitotic cells because of an inherent risk of chromosome rearrangements if the crossovers involve repetitive sequences in the genome. HR is mediated by a class of enzymes known as recombinases. There are two eukaryotic recombinases, RAD51 and DMC1, and both are related to the bacterial recombinase RecA. RAD51 is needed for mitotic and meiotic HR, whereas DMC1 functions only during meiosis. All the recombinases form a helical filament on ssDNA, better known as the presynaptic filament. Assembly of the presynaptic filament requires ATP and is facilitated by recombination mediators, which include the yeast Rad52 protein and the human BRCA2 tumour suppressor. HR is regulated by DNA helicases at several stages. The yeast Mer3 helicase promotes meiotic crossover formation, whereas the yeast Sgs1 and human BLM helicases mediate the dissolution of the double Holliday junction to yield non-crossover recombinants. Moreover, the yeast Srs2 helicase attenuates HR by dismantling the Rad51 presynaptic filament. Many questions concerning the mechanism and regulation of mitotic and meiotic HR remain. For example, how HR functionally synergizes with the Fanconi anaemia protein complex to mediate the removal of interstrand DNA crosslinks remains to be delineated.