Homing in on Hotspots: The clustering of recombination in the genome, around locations known as hotspots, is associated with specific DNA motifs. Now, using a variety of techniques, three studies implicate a chromatin-modifying protein, the histone-methyltransferase PRDM9, as a major factor involved in human hotspots (see the Perspective by Cheung et al. ). Parvanov et al. (p. 835 , published online 31 December) mapped the locus in mice, and analyzed allelic variation in mice and humans, whereas Myers et al. (p. 876 , published online 31 December) used a comparative analysis between human and chimpanzees to show that the recombination process leads to a self-destructive drive in which the very motifs that recruit hotspots are eliminated from our genome. Baudat et al. (p. 836 , published online 31 December) took this analysis a step further to identify human allelic variants within Prdm9 that differed in the frequency at which they used hotspots. Furthermore, differential binding of this protein to different human alleles suggests that this protein interacts with specific DNA sequences. Thus, PDRM9 functions in the determination of recombination loci within the genome and may be a significant factor in the genomic differences between closely related species.

Meiotic recombination is essential for fertility in most sexually reproducing species. This process also creates new combinations of alleles and has important consequences for genome evolution. Meiotic recombination is initiated by the formation of DNA double-strand breaks (DSBs), which are repaired by homologous recombination. DSBs are catalyzed by the evolutionarily conserved SPO11 protein, assisted by several other factors. Some of them are absolutely required, whereas others are needed only for full levels of DSB formation and may participate in the regulation of DSB timing and frequency as well as the coordination between DSB formation and repair. The sites where DSBs occur are not randomly distributed in the genome, and remarkably distinct strategies have emerged to control their localization in different species. Here, I review the recent advances in the components required for DSB formation and localization in the various model organisms in which these studies have been performed.

A partner protein for meiotic snip: Eukaryotes generate germ cells through meiotic recombination. This process initiates through breaks in genomic DNA catalyzed by the SPO11 protein. Vrielynck et al. and Robert et al. discover that SPO11, like topoisomerase VI enzymes, interacts with a partner protein (see the Perspective by Bouuaert and Keeney). This partner is required for proper meiotic recombination and is found in a wide range of eukaryotes, suggesting that it is a universal feature of the essential recombination step. Science , this issue p. 939 , 943 ; see also p. 916

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Meiotic recombination is initiated by the programmed induction of DNA double-strand breaks (DSBs) catalyzed by the evolutionarily conserved Spo11 protein. Studies in yeast have shown that DSB formation requires several other proteins, the role and conservation of which remain unknown. Here we show that two of these Saccharomyces cerevisiae proteins, Mei4 and Rec114, are evolutionarily conserved in most eukaryotes. Mei4^−/− mice are deficient in meiotic DSB formation, thus showing the functional conservation of Mei4 in mice. Cytological analyses reveal that, in mice, MEI4 is localized in discrete foci on the axes of meiotic chromosomes that do not overlap with DMC1 and RPA foci. We thus propose that MEI4 acts as a structural component of the DSB machinery that ensures meiotic DSB formation on chromosome axes. We show that mouse MEI4 and REC114 proteins interact directly, and we identify conserved motifs as required for this interaction. Finally, the unexpected, concomitant absence of Mei4 and Rec114, as well as of Mnd1, Hop2, and Dmc1, in some eukaryotic species (particularly Neurospora crassa, Drosophila melanogaster, and Caenorhabditis elegans) suggests the existence of Mei4–Rec114-dependent and Mei4–Rec114-independent mechanisms for DSB formation, and a functional relationship between the chromosome axis and DSB formation.

PRDM9, a histone lysine methyltransferase, is a key determinant of the localization of meiotic recombination hot spots in humans and mice and the only vertebrate protein known to be involved in hybrid sterility. Here, we report the crystal structure of the PRDM9 methyltransferase domain in complex with a histone H3 peptide dimethylated on lysine 4 (H3K4me2) and S-adenosylhomocysteine (AdoHcy), which provides insights into the methyltransferase activity of PRDM proteins. We show that the genuine substrate of PRDM9 is histone H3 lysine 4 (H3K4) and that the enzyme possesses mono-, di-, and trimethylation activities. We also determined the crystal structure of PRDM9 in its autoinhibited state, which revealed a rearrangement of the substrate and cofactor binding sites by a concerted action of the pre-SET and post-SET domains, providing important insights into the regulatory mechanisms of histone lysine methyltransferase activity.