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Review
. 2014 Oct 16;7(1):a016634.
doi: 10.1101/cshperspect.a016634.

Mechanism and regulation of meiotic recombination initiation

Isabel Lam  1 , Scott Keeney  2
Affiliations
Review

Mechanism and regulation of meiotic recombination initiation

Isabel Lam et al. Cold Spring Harb Perspect Biol. .

Abstract

Meiotic recombination involves the formation and repair of programmed DNA double-strand breaks (DSBs) catalyzed by the conserved Spo11 protein. This review summarizes recent studies pertaining to the formation of meiotic DSBs, including the mechanism of DNA cleavage by Spo11, proteins required for break formation, and mechanisms that control the location, timing, and number of DSBs. Where appropriate, findings in different organisms are discussed to highlight evolutionary conservation or divergence.

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Figures

Figure 1.
Figure 1.
The meiotic recombination pathway. A segment of one sister chromatid from each homolog (black, gray) is shown. Spo11 (ovals) catalyzes DSB formation, in association with partner proteins. Endonucleolytic cleavage on either side of the DSB (black arrowheads) releases Spo11 covalently attached to a short oligonucleotide. The DNA ends undergo 5′-to-3′ resection. A 3′ ssDNA tail invades a homologous duplex DNA and initiates repair synthesis. Repair can proceed by either a double Holliday junction (dHJ) pathway, or synthesis-dependent strand annealing (SDSA). In the dHJ pathway, the second end of the DSB is captured to form a dHJ, and its resolution primarily gives rise to crossover recombinants. Only one cleavage pattern for dHJ resolution is shown (gray arrowheads). In SDSA, the invading 3′ strand is displaced after DNA synthesis and reanneals to the other 3′ end of the DSB, followed by further DNA synthesis and nick ligation, ultimately giving rise to noncrossover recombinant products.
Figure 2.
Figure 2.
Meiotic chromosome organization. (A) Meiotic chromosomes are organized into a series of chromatin loops anchored at their bases by proteinaceous axial elements. (B) At the zygotene stage of prophase I, homologs start to synapse, with the homologous axial elements coming together to form the lateral elements of the synaptonemal complex (SC). The lateral elements are held together by transverse filaments, which, together with central element proteins, make up the central region of the SC. SC formation is completed by the pachytene stage.
Figure 3.
Figure 3.
Interaction maps of DSB proteins in S. cerevisiae and S. pombe, and models for roles of DSB proteins in S. cerevisiae. (A) In S. cerevisiae (left), the 10 proteins required for DSB formation form four interacting subcomplexes (see text for details). Mer2 also interacts with Spp1, which recognizes and binds to H3K4me2/me3 marks on chromatin loops. Mer2 and other DSB proteins localize to the chromosome axes, but it is not known whether this is via interaction with the axial element protein Red1 (dashed arrows and question mark), analogous to the interaction of their homologous proteins in S. pombe. In S. pombe (right), the seven proteins required for DSB formation form two subcomplexes (DSBC and SFT) that interact via Mde2. Rec15 interacts with Rec10, a component of linear elements (LinEs) similar to axial elements in S. cerevisiae. Homologous proteins are shown in the same color for the two species; proteins with no known homologs in the other species are shown in white (except for Spp1, whose homolog in S. pombe is not shown, and whose role in DSB formation is not known). (B) Model for DSB regulation via Mer2 phosphorylation (based on data in Henderson et al. 2006; Sasanuma et al. 2008; Wan et al. 2008; Panizza et al. 2011). Mer2 phosphorylation by the replication-associated kinases CDK-S and DDK leads to recruitment of DSB proteins that directly interact with Mer2 (Rec114, Mei4, Xrs2), and perhaps subsequently also other DSB proteins (Rec102, Rec104, Ski8, Spo11, Mre11, and Rad50). Mer2 (purple) is localized at chromosome axes, along with axial element proteins Red1, Hop1, and cohesin Rec8 (red and gray ovals), but is further enriched at axes on phosphorylation by CDK-S. CDK-S primes Mer2 for further phosphorylation by DDK. Arrows on the chromatin loop represent gene open reading frames. Red squares represent H3K4me3 marks. Only one sister chromatid is shown for clarity. (C) Model integrating DSB formation with loop-axis chromosome structure (based on data in Acquaviva et al. 2012; Sommermeyer et al. 2013). Axis-associated Mer2 interacts with Spp1, which binds H3K4me2/me3 marks and thereby tethers a chromatin loop to the axis. The nucleosome-depleted promoter near the tethered loop segment becomes accessible to Spo11, allowing DSB formation. The precise order of events (Mer2 phosphorylation, loop tethering to the axis) is not known. Spp1 interacts with Mer2 independent of Mer2 phosphorylation, so the potential interactions indicated in the left-most panel (H3K4me2/me3–Spp1–Mer2) could also occur in B, but are not shown.
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