MINIREVIEW From meiosis to postmeiotic events: Alignment and recognition of homologous chromosomes in meiosis Da-Qiao Ding 1 , Tokuko Haraguchi 1,2,3 and Yasushi Hiraoka 1,2,3 1 Kobe Advanced ICT Research Center, National Institute of Information and Communications Technology, Kobe, Japan 2 Graduate School of Frontier Biosciences, Osaka University, Suita, Japan 3 Department of Biology, Graduate School of Science, Osaka University, Toyonaka, Japan Introduction Meiosis is an essential process for sexually reproducing eukaryotic organisms, producing haploid gametes or spores from a diploid cell. In this process, one round of DNA replication is followed by two consecutive nuclear divisions to halve the number of chromosomes. A characteristic feature of meiosis is the behavior exhibited by homologous chromosomes. Homologous chromosomes form a pair and recombine with each other in meiosis, whereas they behave independently in mitotic cell cycles. Meiotic recombination of homolo- gous chromosomes is important for ensuring the cor- rect segregation of chromosomes during the two rounds of nuclear division: reductional segregation of homologous chromosomes in the first division, and equational segregation of sister chromatids in the second division. The process of homologous recombination has been extensively studied at the molecular level (L. Sze ´ kvo ¨ l- gyi and A. Nicolas, this issue [1]), and mechanisms for DNA strand exchange have been determined at atomic resolution (W. Kagawa and H. Kurumizaka, this issue [2]). However, before a pair of homologous DNA strands can interact with each other, they must find each other within the cell nucleus. How chromosomes can find their homologous partners to be paired has been a long-standing question [3–8]. Considering the enormous size of the genome, it is unlikely that DNA sequences are directly compared over the entire gen- ome in the nucleus, like a nucleotide blast search of a database. Instead, the process of homologous recogni- tion may involve chromosome-specific identifiers that can recognize homology at a first glance without com- Keywords bouquet arrangement; double-strand break; homologous chromosome pairing; KASH domain protein; meiosis; recombination; SUN domain protein; synaptonemal complex; telomere; transcription Correspondence Y. Hiraoka, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Japan Fax: +81 6 6879 4622 Tel: +81 6 6879 4620 E-mail: hiraoka@fbs.osaka-u.ac.jp (Received 10 August 2009, revised 21 October 2009, accepted 5 November 2009) doi:10.1111/j.1742-4658.2009.07501.x Recombination of homologous chromosomes is essential for correct reduc- tional segregation of homologous chromosomes, which characterizes meio- sis. To accomplish homologous recombination, chromosomes must find their homologous partners and pair with them within the spatial con- straints of the nucleus. Although various mechanisms have developed in different organisms, two major steps are involved in the process of pairing: first, alignment of homologous chromosomes to bring them close to each other for recognition; and second, recognition of the homologous partner of each chromosome so that they can form an intimate pair. Here, we dis- cuss the various mechanisms used for alignment and recognition of homol- ogous chromosomes in meiosis. Abbreviations DSB, double-strand break; SC, synaptonemal complex; SPB, spindle-pole body. FEBS Journal 277 (2010) 565–570 ª 2009 The Authors Journal compilation ª 2009 FEBS 565 paring nucleotide sequences in detail, e.g. structural fea- tures specific to each chromosome. In fact, pairing of homologous chromosomes involves several cytological steps: spatial alignment of homologous chromosomes accompanied by extensive intracellular rearrangement of chromosomes, dramatic changes in chromosome structures, recognition of homologous chromosomes, recombination of homologous chromosomes, and devel- opment of a structure called the synaptonemal complex (SC), which intimately connects the homologous chro- mosomes along their entire lengths [9] (Fig. 1). Of these steps, it is recognition for which the mechanisms remain largely unknown. Mechanisms dependent on or inde- pendent of double-strand breaks (DSBs) of DNA have both been found. Here, we give an overview of the cur- rent understanding of how homologous chromosomes pair in meiosis. We focus on the mechanisms used for homologous alignment obtained from recent studies in the fission yeast Schizosaccharomyces pombe and the nematode Caenorhabditis elegans, and propose models for homologous recognition. Alignment of homologous chromosomes Pairing of homologous chromosomes occurs at an early stage of meiosis, involves searching for homolo- gous partners, and leads to intimate connections along the entire lengths of homologous chromosomes. At this stage of meiosis, a characteristic arrangement of chromosomes called the ‘bouquet’ arrangement, in which chromosomes are bundled at the telomere to form a bouquet-like arrangement, is observed in a wide variety of organisms [3,4,10–12] (Fig. 1C,D). To form a bouquet arrangement, telomeres are attached to a restricted area of the nuclear envelope, generating a polarized configuration of chromosomes (Fig. 1B–D). These chromosomal events occur during meiotic pro- phase, while the nuclear envelope is intact. An extreme form of the bouquet arrangement has been observed in the fission yeast Schiz. pombe, and the underlying molecular mechanisms have been exten- sively studied in this organism. Schiz. pombe cells nor- mally grow in the haploid state in the presence of sufficient nutrients; upon nitrogen starvation, haploid cells of the opposite mating type conjugate to form a diploid zygote. In a zygote, two nuclei fuse together, and fusion of haploid nuclei is immediately followed by characteristic movements of the elongated nucleus, called a ‘horsetail’ nucleus. The horsetail nucleus moves back and forth between the cell ends for about 2 h. After the nuclear movements cease, two rounds of nuclear division occur. Thus, the horsetail period, cor- responding to meiotic prophase, provides the only opportunity for homologous chromosomes to pair and recombine with their homologous partners. This situa- tion has made Schiz. pombe an attractive experimental system, as we can investigate every event that occurs between homologous chromosomes during the horse- tail period of a few hours. Premeiotic interphase Meiotic prophase A B C D E Fig. 1. Pairing and recognition of homologous chromosomes. Two pairs of homologous chromosomes are shown inside the nucleus, with the centrosome immediately outside the nucleus. Each pair of homologous chromosomes is shown in magenta or green; dark and light lines of the same color indicate homologous chromosomes. Centromeres are indicated by closed circles (A–E). Putative chromosome identifiers are indicated by shaded circles (B, C). (A) During premeiotic interphase, unpaired homologous chromosomes are distributed within the nucleus. (B) Putative chromosome identifiers are formed along each chromosome at the beginning of meiotic prophase. (C, D) After chromo- somes are aligned by bouquet formation, putative chromosome identifiers recognize the homologous partner. (E) A pair of homologous chro- mosomes are synapsed along their entire length at the end of meiotic prophase. Homologous chromosome pairing in meiosis D Q. Ding et al. 566 FEBS Journal 277 (2010) 565–570 ª 2009 The Authors Journal compilation ª 2009 FEBS The Schiz. pombe horsetail nuclear movements are mediated by astral microtubules, which radiate from the spindle-pole body (SPB; a microtubule-organizing center in fungi), and a dynein protein motor [13,14]. The telomeres remain clustered at the leading edge of the moving nucleus throughout the movements [13,15]. Observation of homologous pairing in living meiotic cells has demonstrated that telomere clustering and oscillatory chromosomal movements spatially align homologous chromosomes in the early stages of mei- otic prophase to promote their contact [16]. In the early stages, the arm regions of homologous chromo- somes become close to each other independently of recombination (in the absence of Rec12), and these contacts are stabilized later in a recombination-depen- dent (Rec12-dependent) manner [16,17]. Schiz. pombe Rec12 is a homolog of Saccharomyces cerevisiae Spo11, which is required for DSB formation, and therefore for recombination [18]. At the centromere regions, however, homologous associations gradually increase during the horsetail stage, with similar dynam- ics being observed in both wild-type and rec12 mutant cells, suggesting that pairing at the centromere is stabi- lized in a DSB-independent manner [16]. The ultimate form of pairing is synapsis, which, in many organisms, is accomplished by the formation of the SC, a tripartite structure connecting homologous chromosomes (Fig. 1E). It is known, however, that some organisms do not develop SCs between paired sets of homologous chromosomes, although they are recombined. Schiz. pombe is an example of such organ- isms lacking canonical SCs [19]. In this organism, interestingly, the continuous pulling movements of the chromosomes may compensate for the lack of stable synapsis between homologous chromosomes. Motions of chromosomes for their alignment and pairing The process of homologous chromosome pairing requires mechanisms for finding homologous chromo- somes and, at the same time, preventing non-specific contacts between heterologous chromosomes. During this process, significant motions of chromosomes are expected to occur within the nucleus. It is generally thought that clustering of telomeres, or the bouquet formation, provides a way of promoting homologous pairing by reducing the freedom of movement of chro- mosomes within the nucleus. Subsequently, oscillatory movements of the entire nucleus occur in Schiz. pombe. In some other organisms, intranuclear movements of chromosomes are observed, e.g. in the budding yeast S. cerevisiae [20–23] or in rat spermatocytes [24]. Either kind of chromosomal motion probably has dual roles: first, to act as an attractive force by agitating chromosomes to increase their chance of contact with a homologous partner, and second to act as a repulsive force by disrupting contact between nonhomologous chromosomes. Contacts between homologous chromo- somes would result in a stable, physical link, and the elimination of heterologous chromosomes, and, over time, homologous chromosomes would eventually pair along their entire lengths. Studies in Schiz. pombe have also revealed a mecha- nism for the intranuclear motion of chromosomes [25,26]. Members of conserved families of SUN and KASH domain proteins, Sad1 and Kms1, are involved in the intranuclear chromosomal motions tethering telomeres to the SPB. In general, SUN and KASH domain proteins form a complex that spans the nuclear envelope [27,28]. The Sad1–Kms1 protein complex is localized exclusively at the SPB, but is transiently enriched at the telomeres on the nuclear envelope spe- cifically during the process of bouquet formation (telo- mere clustering). During this process, the Sad1–Kms1 protein complex interacts with telomeres on the nucleo- plasmic side, and with a dynein protein motor on the cytoplasmic side. In this way, telomeres are moved by the driving force generated by the dynein motor on microtubules, which is transmitted by the Sad1–Kms1 protein complex across the nuclear envelope. An interesting mechanism for homologous pairing and recognition has been observed in the nematode C. elegans. In this organism, special nontelomeric regions on chromosomes play a role analogous to telo- meres in bouquet arrangement, and act as a pairing center that promotes pairing and synapsis of the chro- mosomes [29,30]. The pairing center on each chromo- some is bound by one of the four zinc finger proteins HIM-8, ZIM-1, ZIM-2, and ZIM-3, providing a mech- anism for homologous recognition to occur [31,32]. These proteins then attach to the nuclear envelope, where they interact with the SUN and KASH domain proteins, SUN-1 and ZYG-12 [33]. It has been demon- strated that the SUN–KASH protein complex plays a role in moving chromosomes along the nuclear enve- lope using cytoskeletal motor proteins [26,27]. Thus, this mechanism exhibited by the SUN–KASH protein complex is analogous to formation of the bouquet arrangement in Schiz. pombe. Furthermore, recent studies have revealed that similar mechanisms are likely to be involved in intranuclear chromosomal movements in S. cerevisiae [20,21,23,34]. The SUN– KASH protein complex provides a general mechanism for moving chromosomes within the nucleus using cytoskeletal forces through the nuclear envelope. D Q. Ding et al. Homologous chromosome pairing in meiosis FEBS Journal 277 (2010) 565–570 ª 2009 The Authors Journal compilation ª 2009 FEBS 567 Recognition of homologous chromosomes Bouquet formation appears to be a common mecha- nism for the alignment of chromosomes in many organisms. However, the question still remains as to how chromosomes recognize their homologous part- ners. It has been proposed that the interactions between homologous DNAs with DSBs and the con- sequent recombination are involved in homology searching in S. cerevisiae [5]. On the other hand, homologous pairing is independent of recombination in many organisms [5,6]. After chromosomes have been aligned, if each chromosome had a unique pat- tern of blocks of specific molecular components along its length, such a pattern would generate a chromosome-specific barcode, which could act as a chromosome identifier (Fig. 1B,C). Such markers on the chromosome could be recognized at first glance without direct comparison of DNA sequences. Heterochromatin blocks could form such a chromo- some-specific barcode, and so could transcription machinery. In meiosis in male Drosophila, homolo- gous recombination does not occur [35]. In this organism, it is reported that strong pairing sites cor- respond to highly transcribed rDNA loci and histone genes [36]. A previous model proposed roles for transcription and for a specialized transcription fac- tory in homologous chromosome recognition and pairing [37,38]. In this model, DNA regions that are under active transcription are attached to a specific transcription factory, in which transcriptional machinery proteins are aggregated, and those DNA regions that are not undergoing transcription pro- trude from the factory and form a chromatin cloud; therefore, a chromosome appears as a linear array of many factories and clouds. In meiosis, chromosomes are aligned in the chromosome bouquet. Because aligned homologous chromosomes have the same pattern of factories and clouds in parallel, a chroma- tin cloud could also join the factory on its homolog for transcription, and in this way homologous chro- mosomes would be tethered temporally. When many of these temporal interactions occurred, two homolo- gous chromosomes would be zipped up their entire length (Fig. 1C,D). This model provides a possible mechanism for how transcription results in recogni- tion and pairing of homologous chromosomes. A similar model, in which pairing can be achieved through joining of allelic transcription units to the same transcription center, has also been proposed for polyploid plants [39]. Contribution of homologous recombination to pairing Formation of DSBs of DNA is essential for the subse- quent recombination of homologous chromosomes. In meiosis, DSBs of DNA are deliberately generated and healed by recombination between homologous chro- mosomes. On the other hand, pairing and synapsis of homologous chromosomes can be achieved through DSB-dependent or DSB-independent mechanisms. DSB-dependent pairing has been best investigated in the budding yeast S. cerevisiae, and has also been found in animals and plants. In meiosis, DNA DSBs are generated by a type II topoisomerase-like specialized enzyme, Spo11. Spo11 is then removed by the MRX (Mre11–Rad50–Xrs2) complex, and the 5¢-ends of DNA breaks are resected to expose 3¢-single-strand tails; a RecA-type recombinase, Rad51, then binds to the ssDNA and plays a role in searching for DNA that shares sequence homology [5,40]. In S. cerevisiae, about 2100 DSB hot spots have been mapped throughout the genome [41]. It has been proposed that the interactions between homologous DNAs involved in the process of homology searching and recombination along the chro- mosomes allow DSB-dependent pairing to occur [5]. However, even in a mutant lacking Spo11 and other key factors for DSB formation and recombination of DNA, some residual levels of pairing still remain, suggesting that a DSB-independent pairing mechanism may also be operating in this organism [42–44]. On the other hand, typical DSB-independent pairing is found in Drosophila and C. elegans. In these organ- isms, initiation of pairing and synapsis of homologous chromosomes does not depend on DSB formation and recombination, but on the presence of some special chromosomal regions, although the mechanisms are different. In Drosophila males, sex chromosomes pair and segregate without recombination or formation of SCs. A 240 bp repeated sequence within the intergenic spacers of the rRNA genes acts as a cis-acting X–Y pairing site, and is responsible for faithful segregation of X–Y chromosomes [36]. In C elegans, DSBs are not required for homologous pairing [45], and instead a set of four zinc finger proteins, each specifically binding with one or two pairing centers, are essential for pair- ing and synapsis, as described above. In addition, it has been demonstrated that centromere heterochroma- tin plays a role in mediating DSB-independent pairing in organisms such as Drosophila [46], C. elegans [45], and Schiz. pombe [16]. Contribution of homologous recombination to pair- ing may vary among species, depending on the size Homologous chromosome pairing in meiosis D Q. Ding et al. 568 FEBS Journal 277 (2010) 565–570 ª 2009 The Authors Journal compilation ª 2009 FEBS and number of chromosomes, the volume of the nucleus, or the time allowed for pairing. Physical models based on computational simulation provide predictions for contributions of such parameters to the efficiency of homologous chromosome pairing [47–49]. Perspectives Although formation of the bouquet arrangement reduces the spatial distance between homologous chromosomes, which could promote the pairing pro- cess, it does not directly drive recognition of homol- ogous chromosomes. How chromosomes identify their homologous partners remains to be elucidated. The diversity of the underlying mechanisms present in different organisms further increases the complex- ity of this problem [5,6]. In C. elegans, chromosome- specific recognition proteins are linked to cytoskeletal motor proteins to tether homologous chromosomes. In Schiz. pombe, we recently uncovered a novel phe- nomenon relating noncoding RNA to homologous chromosome pairing (D Q. Ding, unpublished results), implying that transcribed RNA mediates rec- ognition of the respective DNA regions of homolo- gous chromosomes. This idea may be supported by the finding that meiotic recombination hotspots coin- cide with loci that express noncoding RNA in Schiz. pombe [50]. 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Ding et al. 570 FEBS Journal 277 (2010) 565–570 ª 2009 The Authors Journal compilation ª 2009 FEBS . MINIREVIEW From meiosis to postmeiotic events: Alignment and recognition of homologous chromosomes in meiosis Da-Qiao Ding 1 , Tokuko Haraguchi 1,2,3 and Yasushi Hiraoka 1,2,3 1. involved in the process of pairing: first, alignment of homologous chromosomes to bring them close to each other for recognition; and second, recognition of the homologous partner of each chromosome. chromosome. In fact, pairing of homologous chromosomes involves several cytological steps: spatial alignment of homologous chromosomes accompanied by extensive intracellular rearrangement of chromosomes,