Break to Make a Connection

Meiosis is the cell division programutilized by most sexually reproducingorganisms as a strategy to produce haploidgametes (i.e., sperm and eggs) from diploidparental cells. As suggested by its name,which stems from the Greek word mean-ing ‘‘to diminish or reduce’’, meiosisreduces the chromosome number by half.This is accomplished by following a singleround of DNA replication with twoconsecutive rounds of cell division (meiosisI and meiosis II). At meiosis I, homologouschromosomes segregate away from eachother (reductional division) and at meiosisII, sister chromatids segregate to oppositepoles of the spindle (equational division).During prophase of meiosis I, chromo-somes undergo a series of unique and well-orchestrated steps that promote accuratesegregation. These steps include the for-mation of programmed DNA double-strand breaks (DSBs), homologous chro-mosome pairing, and synapsis. A subset ofDSBs are repaired via recombinationbetween homologous chromosomes suchthat there is a reciprocal exchange ofgenetic material between the homologsresulting in crossover formation. Thesecrossover events, underpinned by flankingsister chromatid cohesion, generate phys-ical attachments between the homologs(chiasmata), which are important for theirproper alignment at the metaphase I plate.Either impaired DSB formation or afailure to form chiasmata during meiosiscan result in the formation of eggs andsperm carrying an incorrect number ofchromosomes, which in turn accounts fora large percentage of the miscarriages,birth defects, and infertility observed inhumans [1]. Thus, DSB formation is anessential process for successful offspringproduction. Although it is known thatDSB formation is catalyzed by Spo11, aconserved type II topoisomerase-like pro-tein [2,3], the regulation of DSB formationis not completely understood. In this issueof PLoS Genetics, Lake et al. [4] shed newlight on this process by identifying TradeEmbargo (Trem) as a critical protein forDSB production during Drosophila femalemeiosis.Recent studies in yeast have started touncover the molecular basis for the regu-lation of DSB induction. It is known that atleast ten proteins (Spo11-Ski8, Mer2-Mei4-Rec114, Rec102-Rec104, Mre11-Rad50-Xrs2) are essential for DSB induction inSaccharomyces cerevisiae [5]. S phase cyclin-dependent kinase Cdc28–Clb5/Clb6(CDK-S) and the Dbf4-dependent kinaseCdc7–Dbf4 (DDK) regulate the timing ofDSB formation [6,7]. Mer2 is an essentialtarget of both CDK-S and DDK. Specif-ically, Mer2 is phosphorylated by CDK-Sat Ser30. This phosphorylation primesMer2 for subsequent phosphorylation byDDK on Ser29, creating a negativelycharged ‘‘patch’’. This coordinated phos-phorylationtriggerstheinteractionofMer2with Mei4 and Rec114 [6,7]. CDK-S-mediated phosphorylation of Mer2 is alsoimportant for promoting the interactionbetween Mer2 and Xrs2 [8].Thus, pS30ofMer2 recruits the Mre11-Rad50-Xrs2complex to DSB hotspots. Finally, Spo11-Ski8 and Rec102-Rec104 sub-complexesare recruited to the hotspots.Efforts to identify DSB-inducing factorsin other species have been hampered inpart by the low level of sequence conser-vation shared with the factors first identi-fied in S. cerevisiae. However, a sophisticat-ed in silico analysis recently identified theorthologs of Mei4 and Rec114 in fissionyeast, plants, and mammals [9]. Similar toyeast, mei42/2 mice lack meiotic DSBinduction [9]. In mammals, it has beenreported that Prdm9/Meisetz, which is amulti zinc-finger protein that containsKRAB and methyl transferase domains,marks DSB hotspots [10–12]. Moreover,the polymorphism of the zinc fingers altersthe binding activity to hotspot sequences[10,11,12], although Prdm9 is not essen-tial for DSB formation [13]. In othermodel organisms, HIM-17 which is a sixTHAP (C2CH) repeat containing proteinin Caenorhabditis elegans [14], MEI1 [15] inmice, and SWI1 in Arabidopsis thaliana [16]have been reported as factors required forDSB formation. However, how theseproteins act to make DSBs remainsunclear.