Break to Make a Connection

Meiosis is the cell division program utilized by most sexually reproducing organisms as a strategy to produce haploid gametes (i.e., sperm and eggs) from diploid parental cells. As suggested by its name, which stems from the Greek word meaning ‘‘to diminish or reduce’’, meiosis reduces the chromosome number by half. This is accomplished by following a single round of DNA replication with two consecutive rounds of cell division (meiosis I and meiosis II). At meiosis I, homologous chromosomes segregate away from each other (reductional division) and at meiosis II, sister chromatids segregate to opposite poles of the spindle (equational division). During prophase of meiosis I, chromosomes undergo a series of unique and wellorchestrated steps that promote accurate segregation. These steps include the formation of programmed DNA doublestrand breaks (DSBs), homologous chromosome pairing, and synapsis. A subset of DSBs are repaired via recombination between homologous chromosomes such that there is a reciprocal exchange of genetic material between the homologs resulting in crossover formation. These crossover events, underpinned by flanking sister chromatid cohesion, generate physical attachments between the homologs (chiasmata), which are important for their proper alignment at the metaphase I plate. Either impaired DSB formation or a failure to form chiasmata during meiosis can result in the formation of eggs and sperm carrying an incorrect number of chromosomes, which in turn accounts for a large percentage of the miscarriages, birth defects, and infertility observed in humans [1]. Thus, DSB formation is an essential process for successful offspring production. Although it is known that DSB formation is catalyzed by Spo11, a conserved type II topoisomerase-like protein [2,3], the regulation of DSB formation is not completely understood. In this issue of PLoS Genetics, Lake et al. [4] shed new light on this process by identifying Trade Embargo (Trem) as a critical protein for DSB production during Drosophila female meiosis. Recent studies in yeast have started to uncover the molecular basis for the regulation of DSB induction. It is known that at least ten proteins (Spo11-Ski8, Mer2-Mei4Rec114, Rec102-Rec104, Mre11-Rad50Xrs2) are essential for DSB induction in Saccharomyces cerevisiae [5]. S phase cyclindependent kinase Cdc28–Clb5/Clb6 (CDK-S) and the Dbf4-dependent kinase Cdc7–Dbf4 (DDK) regulate the timing of DSB formation [6,7]. Mer2 is an essential target of both CDK-S and DDK. Specifically, Mer2 is phosphorylated by CDK-S at Ser30. This phosphorylation primes Mer2 for subsequent phosphorylation by DDK on Ser29, creating a negatively charged ‘‘patch’’. This coordinated phosphorylation triggers the interaction of Mer2 with Mei4 and Rec114 [6,7]. CDK-Smediated phosphorylation of Mer2 is also important for promoting the interaction between Mer2 and Xrs2 [8]. Thus, pS30 of Mer2 recruits the Mre11-Rad50-Xrs2 complex to DSB hotspots. Finally, Spo11Ski8 and Rec102-Rec104 sub-complexes are recruited to the hotspots. Efforts to identify DSB-inducing factors in other species have been hampered in part by the low level of sequence conservation shared with the factors first identified in S. cerevisiae. However, a sophisticated in silico analysis recently identified the orthologs of Mei4 and Rec114 in fission yeast, plants, and mammals [9]. Similar to yeast, mei42/2 mice lack meiotic DSB induction [9]. In mammals, it has been reported that Prdm9/Meisetz, which is a multi zinc-finger protein that contains KRAB and methyl transferase domains, marks DSB hotspots [10–12]. Moreover, the polymorphism of the zinc fingers alters the binding activity to hotspot sequences [10,11,12], although Prdm9 is not essential for DSB formation [13]. In other model organisms, HIM-17 which is a six THAP (C2CH) repeat containing protein in Caenorhabditis elegans [14], MEI1 [15] in mice, and SWI1 in Arabidopsis thaliana [16] have been reported as factors required for DSB formation. However, how these proteins act to make DSBs remains unclear.