Red-Hed regulation: recombinase Rad51, though capable of playing the leading role, may be relegated to supporting Dmc1 in budding yeast meiosis: Figure 1.

Abstract

DNA strand exchange is the central process of homologous recombination. In budding yeast, this reaction is catalyzed by the recombinases Rad51 and Dmc1. Rad51 is responsible for recombinational repair of DNA damage during mitosis and is also important during meiotic recombination. Dmc1 is only expressed during meiosis and is required for meiotic recombination. The discovery that these two different recombinases are needed for normal levels of meiotic recombination in budding yeast raised the question of how the functions of these proteins relate to one another. The paper by Tsubouchi and Roeder (2006) in this issue of Genes & Development represents important progress toward what is apparently a rather complex answer. Tsubouchi and Roeder (2006) report discovery of a novel meiosis-specific protein, Hed1, which appears to inhibit Rad51 when Dmc1 is absent. The authors show mutation of the HED1 gene allows cells to bypass the meiotic arrest caused by a dmc1 mutation and resolve meiosis-specific double-strand breaks (DSBs) using Rad51. A hed1 mutation can also suppress the defects caused by mutation of HOP2, which codes for a Dmc1 accessory factor. Two-hybrid experiments show that Hed1 and Rad51 can interact directly and immuno-staining shows that subnuclear foci formed by Hed1 and Rad51 colocalize. Together these results imply that Hed1's influence on Rad51 activity is direct. Furthermore, expression of Hed1 in mitotic cells provided evidence that Hed1 expression can be sufficient to inhibit Rad51-dependent repair of mitotic DNA damage.A reasonable interpretation of these results is that the meiotic recombination machinery of budding yeast is regulated such that Dmc1 carries out most strand exchange. Tsubouchi and Roeder's (2006) results also add to evidence indicating that Rad51 is capable of replacing Dmc1's function under certain circumstances. Here, we place these new findings in the context of previous observations and present a model to explain how Rad51 and Dmc1 may cooperate to promote interhomolog recombination in budding yeast, while at the same time accounting for the observed functional redundancy. We further speculate as to how the functional relationship of Rad51 and Dmc1 may have evolved.The notion that Rad51 activity is blocked during meiosis is not new. Previous work showed that Dmc1-independent recombination is inhibited by proteins associated with axial elements (Schwacha and Kleckner 1997;Xu et al. 1997;Bishop et al. 1999;Niu et al. 2005) proteinaceous structures that organize pairs of sister chromatids into two parallel sets of loops by binding at their base. The assembly of the synaptonemal complex brings an axial element with its pair of sisters into close parallel alignment with another axial element holding the homologous sister pair. Three interacting axis-associated proteins-Red1, Hop1, and Mek1-regulate recombination by suppressing Dmc1-independent recombination and, in the case of Red1 and Hop1, by enhancing the efficiency of DSB formation in a locus-specific manner (Rockmill and Roeder...

ASY1 mediates AtDMC1-dependent interhomolog recombination during meiosis in Arabidopsis

“…Studies have demonstrated that the RecA homologs function in a coordinated manner to promote early steps in the meiotic recombination pathway (Neale and Keeney 2006;Sheridan and Bishop 2006), a key feature of which is a preferential bias that ensures that recombination occurs between homologous nonsister chromosomes (Schwacha and Kleckner 1997). In budding yeast, it is proposed that an axis-associated complex of Hop1, Red1, and Mek1 actively suppress DMC1-independent strand invasion during meiosis (Niu et al 2005).…”

“…Nevertheless, efficient repair of all the meiotic DSBs does appear to require Rad51 activity. Hence, it has been proposed that the barrier to intersister repair is eventually lifted, such that Rad51-mediated repair can occur (Sheridan and Bishop 2006). Similarly, in Arabidopsis, AtRAD51 is essential to ensure that the repair of meiotic DSBs is efficient, as DNA fragmentation is observed in an Atrad51 mutant (Li et al 2004).…”

Hed1 regulates Rad51-mediated recombination via a novel mechanism

“…It has been suggested that Red1, Hop1, and Mek1 proteins that are associated with the axial elements suppress Dmc1-independent recombination in an indirect fashion, possibly by influencing the structure of meiotic chromosomes (for review, see Sheridan and Bishop 2006). In contrast, Hed1 appears to regulate meiotic recombination via a direct action on Rad51 (Tsubouchi and Roeder 2006).…”

“…Some of these recombination events lead to the formation of interhomolog crossovers that are crucial for linking the homologous chromosomes, to ensure their proper alignment on the spindle apparatus and faithful disjunction in the first meiotic division. As such, interhomolog crossover recombination is indispensable for the successful execution of meiosis (Keeney et al 1997;Neale and Keeney 2006;Sheridan and Bishop 2006).…”

“…While Rad51 alone is able to repair meiotic DSBs, it has been demonstrated that coordinated function of Rad51 and Dmc1 is required to achieve the meiosis-specific bias for interhomolog recombination (Sheridan and Bishop 2006).…”