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Commentary Introductionhomologs usually enter meiosis unpaired and ‘search’ for homologoussequences during leptotene (Roeder, 1997; McKee, 2004). SummaryHomologous pairing establishes the foundation for accurate reductional segregation during meiosis I in sexual organisms. This Journal of Cell Science 2009). An extreme example is observed in Schizosaccharomyceschromosomes in early meiotic prophase (Ding et al., 2004; Trelles-Schizosaccharomyceshomologous pairing. These findings support the notion thatMost organisms appear to use the type of pairing pathway describedcombination of DSB repair and synapsis (Fig. 1). However, anDrosophilaPairing centers in C. elegansinitially inferred from the effects of reciprocal translocations –(Herman and Kari, 1989; McKim et al., 1993; Villeneuve, 1994).Kari, 1989). These findings suggest that the homologous pairing 1956 Journal of Cell Science 124 (12) ZygoteneP Chromo ABMetase IAnaase I MetasAnaase II Sister chromatid cohesionSpindle KeySC pairs of sister chromatids are shown in the same color. (randomly within the nucleus. At leptotene, telomeres have attachedrandomly along the nuclear envelope. Initially, chromosomes searchfor homologous sequences. This, at first, leads to an approximateparallel alignment of chromosomes. After chromosomes are aligned Box 1. MeiosisMeiosis comprises one round of DNA replication followed by twonuclear divisions, meiosis I and meiosis II (Kleckner, 1996).Meiosis I and II are both divided into five phases: prophase,prometaphase, metaphase, anaphase and telophase. Prophase Imeiosis. It is subdivided into the stages leptotene, zygotene,pachytene, diplotene and diakinesis on the basis of themorphology of chromosomes and the association of homologouschromosomes during synapsis. Several events occur duringprophase I, including DNA double-strand break (DSB) formationand repair, crossover formation, homologous chromosomepairing, synapsis and chromosome condensation. Nuclearenvelope breakdown marks the start of prometaphase I.Meanwhile, homologous centromeres attach to the microtubulesemanating from the spindle poles. The paired homologs(bivalents) are arranged on the equatorial plate at metaphase I.Segregation of homologs to opposite poles initiates at anaphase Iwith the resolution of chiasmata, and the formation of twodaughter cells at telophase I concludes meiosis I. Meiosis II, anequational division that does not reduce chromosome number, isa mitosis-like division. During prophase II, sister chromatidscondense again. The nuclear membrane breaks down atprometaphase II; sister chromatids align at the metaphase plateduring metaphase II and then separate a

t anaphase II. Theprocess ends with telophase II producing four haploid cellscontaining half the original number of chromosomes. ends of chromosomes that contain the PC synapse homologously,pairing pathway, which is supported by the observation thattheir recombination and segregation (Villeneuve, 1994; MacQueenchromosome sites during leptotene and zygotene. The ends of allprophase I, whereas sites that are distant from PCs are largelyunpaired by mid-pachytene. This suggests that PCs function toA second role of PCs is to initiate synapsis, a process that, onceinitiated, is largely homology independent. These roles arePC proteins and target sites in C. eleganscluster. Two of these proteins bind in a chromosome-specificmanner; HIM-8 binds to the PC on the X chromosome and ZIM-2 binds to the PC on chromosome V. The other two proteinsbind to PCs on two different chromosomes – ZIM-1 to both theI and IV. Mutations in the genes that encode these proteins resultand segregation but do not affect the meiotic behavior of autosomes.Interestingly, the phenotypes of mutations are subtly, butconsistently, more severe than the phenotypes that result from theDernburg, 2006).Specific, but similar, target sequences for each of the zinc-fingerthe PC regions of the appropriate chromosomes. These sequencesfinger proteins to their specific chromosomal target sites (Phillips ettarget sequences onto a PC-deficient X chromosome restores HIM-unclear whether the target sequences have any function other thanto form a bridge spanning the nuclear envelope. This mechanismcytoskeletal motor protein, to the nuclear envelope. Subsequently,2C). This movement is thought to facilitate homologous recognition 1957 Meiotic pairing centres Box 2. Synapsis and the synaptonemal complexSynapsis involves the formation of the SC, an elaborate zipper-like structure that connects two aligned homologouschromosomes along their entire length. After homologs recognizeeach other, synapsis enhances and stabilizes these initialassociations by connecting homologous chromosomes until theSC is disassembled at diplotene, when the chromosomes arejoined only by chiasmata. In general, the SC structure isconserved among diverse organisms, although the sequencesimilarity between the protein components is fairly low. The SCcomprises two lateral elements that flank the chromatin, a singlecentral element that is midway between the lateral elements, anda large number of individual transverse filaments that lieperpendicular to the long axis of the complex and act to connectthe lateral elements with the central element (Page and Hawley,2004). The components of the SC structure are crucial forsynap

sis. Synapsis normally occurs between homologouschromosomes; however, the formation of the SC between non-homologous chromosomes, so called non-homologous synapsis,can occur. The processes involved in initial homolog pairingappear to be independent of synapsis. For example, mutations inC. elegans, which encodes an SC structurecomponent, disrupt synapsis but the homologs still align locallyduring early meiosis in these mutants (MacQueen et al., 2002).Furthermore, homolog juxtaposition in yeast is unaffected by theabsence of ZIP1, a component of the central region of SC(Peoples et al., 2002). Box 3. RecombinationMeiotic recombination is initiated by the induction of DSBs onchromosomes by the widely conserved topoisomerase-likeprotein, sporulation-specific protein 11 (SPO11). The DSBs areby the RAD50–MRE11–XRS2 complex togenerate ~300-nucleotide-long 3single-stranded tails. Then,RecA family proteins, which are essential for the repair andmaintenance of DNA, target the ends of the DSBs to formfilaments and catalyze strand-invasion reactions to find a repairtemplate (Pawlowski and Cande, 2005). The DSB repair processleads to gene conversion (the copying of genetic information fromthe repair template into the DSB-bearing homolog) and to theformation of one of two types of products, either crossovers ornon-crossovers. Crossovers result from reciprocal exchangebetween homologous chromosomes and appear as chiasmata,whereas non-crossovers are without reciprocal exchange (Borneret al., 2004). Chiasmata are thought to be the cytologicalmanifestations of crossovers and a chiasma will arise for everycrossover. chromosomes (Sato et al., 2009). However, how homology isis required for SC polymerization. When dynein exerts forces thatmight induce a mechanochemical signal through SUN-1 and characterized the dynamic movements of SUN-1–GFP aggregatesas SUN-1 foci fuse into SUN-1 patches. When homologouschromosomes encounter each other, sufficient affinity betweennon-homologous chromosomes (Fig. 2C). The movement ofDrosophilaDrosophilathe X and Y chromosomes share homology for theribosomal RNA genes (the genes encoding 18S, 5.8S, 2S and 28SThe rRNA genes are present in tandem arrays of 200–250 copieschromosome and near the base of the short arm of the Ychromosome heterochromatin, including the rRNA genes, resultsin a failure of X–Y pairing and high levels of X–Y nondisjunctioncomplete rRNA genes on such X chromosomes substantially restoreX–Y pairing and segregation, indicating that the rDNA functionsas the X–Y pairing site (McKee and Karpen, 1990). Mappingcopies upstream of each rDNA transcription unit (Fig. 3A) (

McKeeet al., 1992). rDNA transgenes that include arrays of these 240-bprDNA transgenes lacking these repeats do not (McKee, 1996).Thus, the X–Y pairing site comprises the 240-bp rDNA repeats.Pairing proteins in DrosophilaThe X–Y pairing site is bound by the two proteins Stromalin in pairing site is bound by the two proteins Stromalin in()of Mdg4 in Meiosis (MNM), which are required for stable homologpairing and segregation in male, but not female, meiosis (Thomaset al., 2005). Both proteins localize to chromosomes throughoutmeiosis I until they suddenly disappear at anaphase I, coincidentwith homolog segregation (Thomas et al., 2005). Thus, theseother and with the 240-bp repeats on the X–Y chromosome pair(Fig. 3B) (Thomas et al., 2005). Moreover, localization of SNMand MNM to the X chromosome is lost when the rDNA genes areinserted (Thomas et al., 2005; Thomas and McKee, 2007). Thesediscussed further below.Do PCs function directly as pairing sites?clear. On the one hand, heterologous pairing or synapsis betweennative chromosomes that share the same PC protein and targetIV, is never observed. On the other hand, multi-copy transgenescomprising large blocks of protein recruitment sequences, wherechromosomes (Phillips et al., 2009). Thus, these sites can function 1958 Journal of Cell Science 124 (12) ZygoteneP Outer nuclearmembrane SC C A NormalReciprocal translocation B General model KeyCytoplasmic forcesSister chromatid cohesionChromosomesSUN-1ZYG-12PC proteinsInner nuclearmembrane Fig. 2. Reciprocal translocation and homologous pairing model in Two pairs of homologous chromosomes are shown. Similar colorsPairs of sister chromatids are shown in the same color. (A reciprocalcapacity and synapsis initiation activity, synapsis in translocationhomologous (different colors). Recombination is suppressed in the non-chromosomes normally separate quickly. When the homologous chromosomeszygotene and pachytene. At post-pachytene stages, the connections between function to test for homology. On the basis of this interpretation,homolog connections (Phillips and Dernburg, 2006). This ismanner similar to telomeres in the bouquet mechanism. Asdirectly.Drosophilapairing of linked non-PC sequences. The best evidence for thisdeficient for native rDNA. All such insertions were effective inpartially restoring X–Y pairing (McKee, 1996). However, becausethe Y chromosome lacks homology to the X euchromatin it is hardinsertions could contribute to pairing. A role for nearby non-PCsequences in pairing of normal X and Y chromosomes cannot beruled out. The 240-bp repeats in these chromosomes are interspersedwith longer rDNA transcription uni

t sequences that are sharedbetween the X and Y chromosomes. These regions could serve asPCs appear to have different roles in thechromosome segregation process betweenorganismsDrosophila2005). However, the term ‘stabilization’ has different meanings inthe two systems. As described above, in interactions and promote synapsis (MacQueen et al., 2005). al., 2005; Phillips and Dernburg, 2006). These observations suggestdispensable for later steps in the homolog segregation pathway.Drosophilaof a bivalent – appear more diffuse when compared with that in thewild type. Subsequently, when chromosomes condense at(Thomas et al., 2005). Moreover, SNM and MNM are retained onZIM proteins. Thus, both SNM and MNM and the HIM-8 and ZIMDrosophilaroles in meiotic chromosome pairing. An interesting question isfor a PC on the X–Y chromosome pair in DrosophilaDrosophilaAutosomes in DrosophilaIn light of the evidence for PC-directed X–Y chromosomal pairing,Drosophilamale meiosis involves specific sites (Vazquez et al., 2002). However,Drosophilapairing capacity. However, they do not rule out the possibility ofregions) in centric heterochromatin. A recent fluorescent in situregions of the major autosomes (Tsai et al., 2011), thus providingHowever, the small fourth chromosomes did remain paired at a 1959 Meiotic pairing centres XLXR AB rDNA TU 28S5.8S 2S 18S 28S 18S ETS ITS HeterochromatinEuchromatin240-bp repeatsCentromererDNASNM–MNMKey IGS IGS Fig. 3. X–Y chromosome pairing in rDNA transcription unit (TU) and intergenic spacer (IGS) region comprise acomplete rDNA unit. Each rDNA TU consists of the 18S, 5.8S, 2S and 28S(ITS). Transcription units are separated by IGSs. The IGS comprises severallocated immediately upstream of the rDNA TU in each rDNA repeat. (X and Y chromosomes are shown schematically, with heterochromatic regionsovals. rDNA loci are located in the central region of the X heterochromatinand near the base of the short arm of the Y heterochromatin. SNM and MNMof the X chromosome; XR, the right arm of the X chromosome; YS, the shortarm of the Y chromosome; YL, the long arm of the Y chromosome. Drosophilaallelic pairing at the mid-G2 transition. The autosomal homologsindicates that an unknown factor could keep them together. SNMet al., 2005) (J.-H.T., unpublished results), but the binding sites ofupon the Teflon (TEF) protein, which is required for segregationof the autosomes but not the sex chromosomes (Tomkiel et al.,2001; Thomas et al., 2005). We have suggested, by analogy tobetween autosomal homologs exist at different sites in differentmeiotic cells (Tsai et al., 2011). Time-lapse analyses in livinghap

pened to lie sufficiently close to a tagged chromosomal siteBoundary sites appear not to function in pairing inDrosophila femalesUntil recently, Drosophiladiscredited this idea. As in , the ‘pairing sites’ inDrosophilastudy, X recombination was found to be suppressed in a distinctfrequencies elsewhere on the X chromosome (Hawley, 1980).sites’. As the translocation breakpoints disrupted recombinationintervening region (Hawley, 1980). A recent study found similaret al., 2005). However, molecular analysis of pairing in femaleset al., 2005). Thus, if the boundary sites identified in the previousto be more subtle than originally hypothesized. At least withinDrosophilaPairing centers: common features of meioticchromosomes?DrosophilaMoreover, nothing similar to the PCs of Drosophilaorganisms. Nevertheless, as summarized below, phenomenachromosomal sites, including nucleolus organizer regions (NORs),telomeres and centromeres. As noted above, telomere meioticHowever, the data on centromere pairing are particularly intriguingand will be analyzed in some depth below.Nucleolus organizer regionsor synapsis. In organisms in which preferential synapsis initiation(Page and Hawley, 2004). Indeed in budding yeast, NORs areapparently excluded from synapsis (Tsubouchi et al., 2008).However, PC-like behavior has been reported for NORs in homologous-pairing protein 2(HOP2), which is conserved amongyeast, animals and plants and has been shown, in several organisms,and synapsis at most genomic sites. However, the short arms ofnormal pairing frequencies and normal SC formation. ThesePCs. The extent to whichorganisms, still remains to be determined.Centromeres and centric heterochromatinvariety of organisms (reviewed by Stewart and Dawson, 2008). Inbudding yeast and wheat (Martinez-Perez et al., 1999; Tsubouchiand Roeder, 2005). In both of these cases, however, early pairwiserandom ‘couplings’ of centromeres, with the pairings becominghomologous as cells proceed through meiotic prophase. However, 1960 Journal of Cell Science 124 (12) center of the chromosome. This suggests that the homology at(Corredor et al., 2007). Moreover, when the wheat centromeres arethere is no effect on the pairing patterns in wheat nuclei, indicatingnon-homologous chromosomes. Similarly, interchromosomal‘centromere swaps’ have no effect on meiotic chromosome pairingRemarkably, however, in budding yeast, these non-homologousbeen largely replaced by homologous associations), a majority ofcentromere or incorporate a centromere within them. This isbidirectionally (Tsubouchi et al., 2008). Moreover, ZIP1 localizeson ZIP1 (Tsubouchi and Roeder, 2005). T

hus, centromeres in yeastprophase, after the disassembly of the SC in a number of organismsDrosophilamoderate efficiency (Kemp et al., 2004). Recent evidence showsprophase couplings described above, require ZIP1. Moreover, loss(Gladstone et al., 2009). In the same study, it was also found thatcentromeres to opposite poles. Thus, the budding yeast centromereDrosophilathe segregation of achiasmate homolog pairs (Dernburg et al.,Drosophilaosophilanon-exchange X chromosomes segregate preferentially from othernon-exchange X chromosomes, rather than from a non-exchangenon-homolog (Hawley et al., 1992)]; this is also more efficient asit yields segregation frequencies of ~100% in many cases. However,Drosophilais diffusely distributed throughout large tracts of centric1996). The involvement of such extensive regions probably explainsDrosophilaand could also contribute to its high efficiency. Thus, although theDrosophilathemselves have in this process. An interesting possibility is thatcentromere associations do occur, perhaps non-homologously, asand, eventually, enable the formation of stable connections withinInterestingly, Drosophilachromosome arms (Vazquez et al., 2002; Yan et al., 2010). A recent(Tsai et al., 2011), and thus could be an example of PC-likebehavior. However, homologous centromere pairing is short-lived;unpaired throughout the remainder of meiosis I. The functionalhomology dependence is unknown. Centromeres of differentDrosophilachromosomes appear not to share DNA sequencesuch specificity. Alternatively, the specificity could be entirelyterritories, so that, when they pair, it is probable that a centromereand specifically with each other, but that such pairings are generallyWe have described two prominent examples of the use of PCs torecruitment sites for specialized pairing proteins. However, thepairing proteins and sites function somewhat differently in the twoDrosophila non-homologous X–Y chromosome pair and a unique proteinthereby providing stable inter-homolog connections. Surprisingly,however, Drosophila 1961 Meiotic pairing centres question is how homolog alignment is translated into stable inter-despite occupying a common territory. Another is how SNM andMNM are recruited to autosomes. Finally, it remains to bedetermined how specific connections between the four differentsystem. The precise role of the PCsolution to the pairing problem. In most organisms, cytological andPawlowski, 2008; Roeder, 1997). Nevertheless, most organisms dochromosome pairing, synapsis and segregation. Telomeres do notchoice in many organisms, a role that seems remarkably similar,mechanistically, to that played by PCs in . However,cent

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