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Branching Out: Meiotic Recombination and Its Regulation TICB-453; No of Pages 8 Review TRENDS in Cell Biology Vol.xxx No.x Branching out: meiotic recombination and its regulation Gareth A. Cromie and Gerald R. Smith Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA Homologous recombination is a dynamic process by parental chromosome segregation during the first meiotic which DNA sequences and strands are exchanged. In division. The COs link the homologous chromosomes phy- meiosis, the reciprocal DNA recombination events called sically so that they can be oriented correctly on the meiotic crossovers are central to the generation of genetic diver- spindle. In the absence of COs, chromosomes often mis- sity in gametes and are required for homolog segregation segregate, resulting in aneuploid gametes and offspring. in most organisms. Recent studies have shed light on how Recent studies have advanced our understanding of how meiotic crossovers and other recombination products meiotic COs and NCOs form, how they are distributed form, how their position and number are regulated and across genomes, and how the pair of DNA molecules under- how the DNA molecules undergoing recombination are going a CO is chosen. In this review, we focus on how chosen. These studies indicate that the long-dominant, advances in these three areas have challenged several core unifying model of recombination proposed by Szostak features of long-accepted models, revealing many new et al. applies, with modification, only to a subset of branches of the meiotic recombination ‘pathway’. Most recombination events. Instead, crossover formation and significantly, the mechanism of recombination associated its control involve multiple pathways, with considerable with the well-known DSB repair model of Szostak et al. [1] variation among model organisms. These observations (hereafter called the Szostak model), long believed to force us to ‘branch out’ in our thinking about meiotic explain all meiotic recombination, applies only to the recombination. formation of COs and not to NCOs. A particular theme of recent advances is that a full understanding of recombi- Introduction nation can be gained only by synthesizing insights from Homologous recombination is the process by which DNA different model organisms. loci of nearly identical nucleotide sequences interact and exchange DNA structure and sequence information. The Szostak model of recombination Recombination is an aspect of DNA metabolism conserved The modified Szostak model of recombination [1,2] has from viruses to humans and has two major roles. First, dominated modern thinking about the mechanism of meio- recombination is a universally important mechanism for tic recombination. It involves a single pathway of DNA the repair of DNA double-strand breaks (DSBs), which intermediates that produces both COs and NCOs occur frequently because of DNA damage, such as replica- (Figure 1a), consistent with the existence of several tion-fork breakage. Second, in eukaryotes, recombination mutations that impair both CO and NCO formation (but is central to meiosis, the process by which diploid cells give see later). The Szostak model predicts that recombination is rise to haploid gametes, such as eggs, sperm and fungal initiated by DNA DSBs. Each DSB produces two duplex spores. ends that are processed to give single-stranded overhangs. A recombination event between two loci can result in Single-end invasion (SEI) then occurs, in which one of the one of two different outcomes: crossovers (COs) or non- two processed ends of the DSB (the right end in Figure 1a) crossovers (NCOs). In COs, the two strands of each hom- invades a homologous duplex, giving a displacement-loop ologous duplex are reciprocally broken and joined, causing (D-loop) structure. Next, the second processed end of the exchange of alleles flanking the CO position; in NCOs, no DSB (the left end in Figure 1a) anneals to the D-loop. The such rearrangement occurs and flanking alleles maintain resulting joint molecule undergoes repair DNA synthesis to their original linkage (Figure 1). Both COs and NCOs can fill in single-strand gaps and is held together by two struc- be accompanied by localized non-reciprocal ‘donation’ of tures in which strands are exchanged between the interact- sequence information from one homologous locus to ing duplexes. These structures are called Holliday junctions another, termed ‘gene conversion’. (HJs) individually, together forming a double Holliday junc- In meiosis, COs occurring between homologous tion (dHJ) structure. Cleavage of pairs of strands in each chromosomes are particularly important because they gen- HJ (‘resolution’) in one of two orientations (Figure 1aiii), erate genetic diversity in the gametes and, after fertiliza- chosen at random, produces COs or NCOs depending on tion, in the offspring. In most organisms, interhomologue which combination of cleavage orientations (‘1’ or ‘2’ in COs are also required for the unique mechanism of Figure 1a iii) occurs at the two HJ sites. Gene conversions arise because of mismatch repair in regions of heteroduplex Corresponding author: Cromie, G.A. ([email protected]). DNA in the joint molecule and so can be associated with Available online xxxxxx. either the CO or NCO outcome, as observed experimentally. www.sciencedirect.com 0962-8924/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2007.07.007 Please cite this article in press as: Cromie, G.A. and Smith, G.R., Branching out: meiotic recombination and its regulation, Trends Cell Biol. (2007), doi:10.1016/j.tcb.2007.07.007 TICB-453; No of Pages 8 2 Review TRENDS in Cell Biology Vol.xxx No.x Figure 1. Szostak model of CO and NCO formation and the synthesis-dependent strand-annealing (SDSA) model of NCO formation. (a) In the Szostak model, a DSB occurs on one homologous chromosome (blue) and the two duplex ends of this DSB are processed to form single-strand 30 overhangs (i). One end of the DSB invades another homologous chromosome (red) and sets up a SEI or displacement-loop (D-loop) structure (ii). DNA synthesis extends the D-loop and enables annealing of the second side of the DSB. Further DNA synthesis fills in the remaining gaps and a double HJ structure is formed (iii). Cleavage and re-annealing, or ‘resolution’, of either pair of like- oriented strands in each HJ (‘1’ or ‘2’), occurs at random. In the figure, the leftward HJ has been resolved in orientation ‘1’; resolution of the rightward HJ in orientation ‘1’ then produces a NCO (iv) and in orientation ‘2’ a CO (v). Note that, in the Szostak model, newly replicated DNA (broken lines) occurs on both homologous chromosomes, terminated at the DSB site on each (iii). (b) In the SDSA model, a DSB is formed and processed as in the Szostak model (i). One end of the DSB transiently invades another homologous chromosome and is extended by DNA synthesis (ii). This end then pulls out and the newly synthesized extension anneals with the other end of the DSB (iii). Further repair DNA synthesis occurs and a NCO is formed (iv). No HJ resolution has occurred. Note that, in the SDSA model, newly replicated DNA (broken lines) occurs only on one homologous chromosome and spans the DSB site (iii). In both models, gene conversions can occur by mismatch correction in any region of heteroduplex DNA, shown as duplexes containing one blue and one red strand. Some predicted intermediates of the Szostak model, through different DNA intermediates to produce either such as DSBs and dHJs, have been observed in the budding COs or NCOs [7–10]. These new conclusions are based yeast Saccharomyces cerevisiae and DSBs have also been on the study of mutations affecting steps in recombination detected in the fission yeast Schizosaccharomyces pombe occurring after DSB formation and processing and on the and inferred in mice [2–6]. However, recent work in differ- study of physical recombination intermediates and pro- ent model organisms has led to the conclusion that the ducts. Szostak model is not a general model for meiotic recombi- One prediction of the Szostak model is that COs and nation but applies, with revision, only to CO formation. NCOs should occur at the same time. Using physical assays in budding yeast, a study of ectopic recombination COs and NCOs arise through different branches of the events [7] showed that this is not true and that NCOs form recombination pathway before COs. Similarly, repair DNA synthesis associated Mutations preventing DSB formation or processing with NCOs in budding yeast occurs earlier than does that eliminate both COs and NCOs, indicating that early steps associated with COs [9]. in CO and NCO formation proceed by the same pathway. In DSBs are precursors to both COs and NCOs, but the the Szostak and previous models, the branching of the other observed intermediates of the Szostak model (D- recombination pathway to produce COs or NCOs was loops and dHJs) appear to lie only on the CO pathway. hypothesized to occur at a very late stage. In these models, In budding yeast, the timing of dHJ appearance and dis- NCOs and COs both arise from the same HJ-containing appearance compared with the timing of CO and NCO intermediate, depending on the orientation of HJ resol- formation suggests that dHJs are precursors only of COs ution (Figure 1a). An important conclusion of recent stu- [7]. Mutants with reduced SEI or dHJ formation have dies is that this idea is incorrect and that, instead, the reduced CO but not NCO frequency [10]. In both fission pathway branches soon after DSB formation and proceeds [11,12] and budding [7] yeasts, mutations causing defects www.sciencedirect.com Please cite this article in press as: Cromie, G.A. and Smith, G.R., Branching out: meiotic recombination and its regulation, Trends Cell Biol.
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