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The Choice in Meiosis – Defining the Factors That Influence Crossover Or Non-Crossover Formation

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The Choice in Meiosis – Defining the Factors That Influence Crossover Or Non-Crossover Formation Commentary 501 The choice in meiosis – defining the factors that influence crossover or non-crossover formation Jillian L. Youds and Simon J. Boulton* DNA Damage Response Laboratory, Cancer Research UK, London Research Institute, Clare Hall, Blanche Lane, South Mimms EN6 3LD, UK *Author for correspondence ([email protected]) Journal of Cell Science 124, 501-513 © 2011. Published by The Company of Biologists Ltd doi:10.1242/jcs.074427 Summary Meiotic crossovers are essential for ensuring correct chromosome segregation as well as for creating new combinations of alleles for natural selection to take place. During meiosis, excess meiotic double-strand breaks (DSBs) are generated; a subset of these breaks are repaired to form crossovers, whereas the remainder are repaired as non-crossovers. What determines where meiotic DSBs are created and whether a crossover or non-crossover will be formed at any particular DSB remains largely unclear. Nevertheless, several recent papers have revealed important insights into the factors that control the decision between crossover and non-crossover formation in meiosis, including DNA elements that determine the positioning of meiotic DSBs, and the generation and processing of recombination intermediates. In this review, we focus on the factors that influence DSB positioning, the proteins required for the formation of recombination intermediates and how the processing of these structures generates either a crossover or non-crossover in various organisms. A discussion of crossover interference, assurance and homeostasis, which influence crossing over on a chromosome-wide and genome-wide scale – in addition to current models for the generation of interference – is also included. This Commentary aims to highlight recent advances in our understanding of the factors that promote or prevent meiotic crossing over. Key words: DSB repair, Meiosis, Crossover control, Homologous recombination Introduction overhangs that are initially bound by replication protein A (RPA), Meiosis is the specialised reductive division that generates haploid which is subsequently displaced by the recombinase radiation cells. During this process, a single round of replication is followed sensitive 51 (RAD51) and/or the meiosis-specific recombinase by two rounds of chromosome segregation: in the first division dosage suppressor of Mck1 (DMC1) to form nucleoprotein (meiosis I), homologous chromosomes segregate, whereas in the filaments. These filaments serve to find a complimentary sequence Journal of Cell Science second division, sister chromatids segregate (meiosis II). A key within a homologous chromosome, at which they instigate single- step in meiosis I is the recognition of homologous chromosomes, end strand invasions (Hunter and Kleckner, 2001) to generate so- which then align and pair along the length of the chromosome. called displacement loop (D loop) recombination intermediates Once homologues have aligned, synapsis can proceed with the (Fig. 1). If the second end of the original DSB binds with the formation of the synaptonemal complex (SC), a protein structure homologous chromosome, a double Holliday junction is formed, that supports and maintains homologues in close juxtaposition and which can be resolved to generate either a non-crossover or an serves as a scaffold for crossover-promoting recombination factors. interhomologue crossover, the latter of which is hereafter referred Meiotic crossing over involves the generation of meiotic double- to simply as crossover (Bishop and Zickler, 2004; Schwacha and strand breaks (DSBs), which are subsequently repaired either as Kleckner, 1995). Double Holliday junctions can also be processed crossovers or non-crossovers (Fig. 1). Meiotic recombination is through dissolution, which results in a non-crossover (Fig. 1) (Wu not only necessary to create new allele combinations that generate and Hickson, 2003). Meiotic non-crossovers have also been genetic diversity, but is also essential in ensuring accurate proposed to form when strand invasion is transient, and when a chromosome segregation at the first meiotic division because the limited amount of DNA synthesis occurs before the invaded strand crossover acts as a tether between homologues, which ensures that dissociates and anneals to its partner strand, as in mitotic synthesis- each homologue will properly align at the metaphase plate and dependent strand annealing (SDSA; see Box 1 and Fig. 1) (Allers thereby correctly attach to the spindle. DSB repair occurs and Lichten, 2001; Bishop and Zickler, 2004). During meiosis in concurrently with SC formation and is required for normal synapsis budding yeast, non-crossover heteroduplex products are found to in yeast and mice (Baudat et al., 2000; Roeder, 1997; Romanienko form with the same timing as double Holliday junctions, whereas and Camerini-Otero, 2000), whereas in Caenorhabditis elegans crossovers occur later (Allers and Lichten, 2001), consistent with and Drosophila melanogaster, homologue pairing and SC formation the idea that crossovers and non-crossovers are formed through can occur independently of meiotic recombination (Colaiacovo et distinct pathways. Analysis of ZMM mutants (Zip1, Zip2, Zip3, al., 2003; Dernburg et al., 1998; Liu et al., 2002; McKim et al., Zip4, Mer3, Msh4 and Msh5; further discussed below) in yeast 1998). indicates that the decision between crossover and non-crossover is The process of meiotic recombination is initiated when meiotic made very early, i.e. at or prior to the establishment of a stable DSBs are created by the endonuclease SPO11, in conjunction with single-end invasion intermediate, when one of the two ends of the a number of additional proteins (Keeney and Neale, 2006). DSBs DSB invades its homologous chromatid (Bishop and Zickler, 2004; are then resected to generate 3Ј single-strand DNA (ssDNA) Borner et al., 2004; Hunter and Kleckner, 2001). Thus, the 502 Journal of Cell Science 124 (4) Double-strand-break formation Single-end invasion 3Ј 3Ј 5Ј 5Ј 5Ј 3Ј D loop recombination intermediate Double Holliday junction Fig. 1. Model for meiotic crossover or non-crossover formation. Double strand breaks are generated and their 5Ј ends are resected to generate a 3Ј overhang. A strand invasion event then generates a single-end invasion D loop intermediate. If the second end of the original DSB also engages with the homologue, a double Holliday junction is formed (shown on the left). The double Double Holliday Double Holliday SDSA Holliday junction can be resolved to form either a junction resolution junction dissolution crossover (interference-dependent) or a non-crossover. Alternatively, the junction can be dissolved by double Holliday junction dissolution to form a non-crossover. Instead of forming a double Holliday junction, the D Crossover Non-crossover Crossover loop can be dissociated and the invading strand can (interference-dependent) (interference-independent) or associate with the opposite end of the original break, as in synthesis-dependent strand annealing (SDSA), to form a non-crossover. Alternatively, the intermediate can be acted upon by enzymes such as Mus81 that can form Non-crossover Non-crossover interference-independent crossovers. Journal of Cell Science crossover–non-crossover decision is thought to occur around the Several studies have shown that Spo11 access to DNA is one of time of strand exchange. the determinants of DSB location, because DSBs are often found This Commentary will discuss the factors that contribute to within open chromatin in yeast (Berchowitz et al., 2009; Ohta et crossover or non-crossover formation in meiosis, including the al., 1994; Wu and Lichten, 1994). In C. elegans, the putative generation and positioning of meiotic DSBs, formation of the SC chromatin-modifying protein high incidence of males 17 (HIM- and generation of recombination intermediates. We will also discuss 17) is required for successful DSB formation and for normal levels how interhomologue crossing over is promoted compared with of dimethylation of lysine residue 9 of histone 3 (H3K9Me2) intersister repair, how recombination intermediates are resolved during meiosis, because mutants display a marked reduction in into crossovers as well as how anti-recombinases prevent crossing H3K9Me2 staining (Reddy and Villeneuve, 2004). Furthermore, over. Crossover interference, assurance and homeostasis will also DSB formation in him-17 non-null mutants can be enhanced by be discussed (see text box), including a summary of the current loss of LIN-35, the C. elegans retinoblastoma (Rb) protein models for how crossover interference is established. homologue, which is a known component of chromatin modifying complexes (Reddy and Villeneuve, 2004). Collectively, these data Control of meiotic DSB formation suggest that the activity of HIM-17 alters the chromatin state, Meiotic crossovers tend to form at specific sites in the genome of probably by opening the chromatin to allow access by SPO-11, most organisms (Buard and de Massy, 2007; Mezard, 2006; Pryce and this governs DSB competence. More recently, components of and McFarlane, 2009); these are known as recombination hotspots. the C. elegans condensin I complex have been implicated in In mammals, hotspots are typically regions of 1–2 kb that occur regulating both the position and number of DSBs, because mutants every 50–100 kb within the genome (Jeffreys et al., 2001; McVean, show increased formation of meiotic DSBs and a distribution of 2010; Myers et al., 2008). Human recombination
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