Chromosome Choreography: The Meiotic Ballet

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THE DYNAMIC CHROMOSOME 38. P. S. Lee, D. Lin, S. Moriya, A. D. Grossman, J. Bacteriol. 185, 1326 (2003). 39. Y. Li, K Sergueev, S. Austin, Mol. Microbiol. 46, 985 (2002). 40. H. Niki, Y. Yamaichi, S. Hiraga, Genes Dev. 14, 212 (2000). 41. P. J. Lewis, J. Errington, Molec. Microbiol. 25, 945 (1997). 42. B.-H. Sigal, D. Z. Rudner, R. Losick, Science 299, 532 (2003). 43. C. E. Helmstetter, in Escherichia coli and Salmonella: Cellular and Molecular Biology, F. C. Neidhardt et al., Eds. (ASM Press, Washington, DC, 1996), pp. 1627– 1639. The eukaryote cell-cycle nomenclature is applied to bacteria for clarity. S corresponds to C period (DNA synthesis phase) and G2-M to the D period

(period from completion of replication to the completion of cell division). G1 is the period from birth of a newborn cell to the beginning of S. 44. Y. Sunako, T. Onogi, S. Hiraga, Mol. Microbiol. 42, 1223 (2001). 45. I thank the many colleagues who have provided the data and ideas that have made this review possible. Also, I thank members of my own group for hard work and inspiration. In particular, I thank S. Filipe and J. Yates for help in preparing the figures. My research is supported by the Wellcome Trust. As a consequence of the limited length of this report, literature citations have been limited to recent relevant reviews and research reports; I apologize to those authors whose important work has not been cited directly.

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28. K. Kobryn, G. Chaconas, Curr. Opin. Microbiol. 4, 558 (2001). 29. G. R. Weller et al., Science 297, 1686 (2002). 30. J. Dworkin, R. Losick, Proc. Natl. Acad. Sci. U.S.A. 99, 14089 (2002). 31. F. van den Ent, L. A. Amos, J. Lowe, Curr. Opin. Microbiol.4, 634 (2001). 32. W. Margolin, Curr. Opin. Microbiol. 4, 647 (2001). 33. L. J. Jones, R. Carballido-Lopez, J. Errington, Cell 104, 913 (2001). 34. E. J. Harry, Mol. Microbiol. 40, 795-803 (2001). 35. K. Gerdes, J. Moller-Jensen, R. B. Jensen, Mol. Microbiol. 37, 455 (2000). 36. J. Moller-Jensen, R. B. Jensen, J. Lowe, K. Gerdes, EMBO J. 21, 3119 (2002). 37. S. Autret, J. Errington, Mol. Microbiol. 47, 159 (2003).

REVIEW

Chromosome Choreography: The Meiotic Ballet Scott L. Page and R. Scott Hawley* The separation of homologous chromosomes during meiosis in eukaryotes is the physical basis of Mendelian inheritance. The core of the meiotic process is a specialized nuclear division (meiosis I) in which homologs pair with each other, recombine, and then segregate from each other. The processes of chromosome alignment and pairing allow for homolog recognition. Reciprocal meiotic recombination ensures meiotic chromosome segregation by converting sister chromatid cohesion into mechanisms that hold homologous chromosomes together. Finally, the ability of sister kinetochores to orient to a single pole at metaphase I allows the separation of homologs to two different daughter cells. Failures to properly accomplish this elegant chromosome dance result in aneuploidy, a major cause of miscarriage and birth defects in human beings. Meiosis creates haploid daughters from a diploid parental cell in a manner that ensures each daughter cell a complete haploid genome. This is accomplished by first pairing homologous chromosomes to identify partners and then segregating these partners away from each other at the first meiotic division (meiosis I). Meiosis I is followed by a second mitosis-like division in which sister chromatids separate from each other. Errors in meiosis occur in as many as one in four human oocytes, resulting in the production of aneuploid zygotes (i.e., zygotes with an incorrect chromosome number), and the frequency of errors in maternal meiosis I increases with maternal age (1). The consequences of such errors can be devastating: Aneuploidy is a factor in ⬃35% of spontaneous pregnancy losses and is the most common recognized cause of mental retardation. In the last two decades, our understanding of the mechanisms that underlie meiotic recombination, and allow recombination events to ensure chromosome segregation, has increased dramatically, as has our unStowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. *To whom correspondence should be addressed. Email: [email protected]

derstanding of the structure of the synaptonemal complex (SC), a proteinaceous structure that connects paired chromosomes. However, we still know very little about the mechanisms that underlie chromosome pairing or the mechanisms by which the SC maintains bivalent stability and facilitates reciprocal meiotic exchange. Although the goal of this review is to both elucidate the areas that are well understood and describe the unanswered questions, we will need to do so primarily in terms of the most common meiotic systems: those in which pairing leads to synapsis, synapsis facilitates the completion of recombination, and recombination ensures segregation (Fig. 1).

Pas de Deux: Homologous Chromosome Pairing Homologous chromosomes are brought together by a number of chromosome pairing and alignment mechanisms, which can generally be divided into mechanisms that require DNA double strand break (DSB) formation and those that are DSB-independent. The DSB-dependent class of mechanisms likely involves a homology search directly on the basis of DNA sequence. In Saccharomyces cerevisiae, DSB formation and early recombination intermediates are

required to establish a stable pairing interaction between homologs (2). This juxtaposition of homologous chromosomes was shown to be distinct from SC-mediated pairing and likely uses the recombination pathway for its establishment. In contrast, DSB-independent processes might include mechanisms such as the maintenance of premeiotic pairings or the pairing of homologs on the basis of the aggregation of sequence-specific DNA binding proteins. Both of these mechanisms can and usually do lead to synapsis, the stage at which the SC connects the two homologs that comprise the mature bivalent along their lengths. The degree to which DSB-dependent and DSB-independent pairing mechanisms are used in meiosis appears to vary among organisms. For example, along with DSBbased pairing, S. cerevisiae also uses at least some types of homolog-pairing interactions that occur in the absence of both DSBs and the SC, although additional mechanisms may be required to stabilize those interactions (2, 3). Indeed, substantial homolog pairing is detected in yeast expressing a catalytically inactive version of Spo11p, the protein responsible for generating meiotic DSBs (4 ). The finding that deletion of this protein abolishes pairing altogether suggests a structural role for Spo11p in chromosome pairing beyond that of initiating recombination by creating DSBs (5). Similarly, in the basidiomycete Coprinus cinereus, a substantial amount of homolog pairing occurs in the absence of meiotic DSBs (6 ), despite the fact that DSBs are essential for proper synapsis. At the other end of the spectrum, homolog pairing occurs normally in the complete absence of DSBs in Caenorhabditis elegans and in both sexes of Drosophila (7–10).

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Are there specific pairing elements or Synapsis requires DSB formation in identified that disrupt telomere clustering sites? A number of sites or regions have most organisms. In a large number of orand/or separation and various aspects of been identified that appear to facilitate ganisms, the initiation of synapsis requires pairing, synapsis, or recombination (17, pairing. The one commonality of these rethe creation of DSBs by Spo11p (3, 5). 18). Perhaps the ability of telomeric regions is that they all map near to or are DSBs are essential for synapsis in S. cergions to function as pairing elements may comprised by repetitive sequences. The evisiae, and similar observations have been also reflect the aggregation of proteins that best characterized of these pairing sites is a made in Arabidopsis and in mammalian bind specifically to these sequences. 240-base-pair repeat sequence in the interspermatocytes (5). A specific requirement Pas de Quatre: Synaptonemal genic spacer found between ribosomal for DSB formation to execute synapsis is Complex Formation RNA genes clustered on the Drosophila X suggested by the observation in Coprinus In most organisms, pairing events appear to and Y chromosomes. When present in muland in mice that the synapsis defect obbe stabilized by a tight axial association tiple copies, this sequence facilitates the served in the absence of a functional Spo11 called synapsis, in which the four chromatids pairing and subsequent segregation of the X protein can be rescued by experimentally and Y chromosomes during induced DSBs. Induction meiosis in Drosophila males of DSBs by gamma irradi(11). One can imagine that ation rescues the synapsis this represents a case where defect in the Coprinus the aggregation of proteins spo11 mutant (6 ), and cisthat bind to specific sites (in platin-induced DSBs cause this case, nucleolar proteins) a partial restoration of synserves both to pair chromoapsis in spo11–/– mutant male mice (19). SC forms somes and to maintain the to a varying degree in yeast connection between them. mutants defective for the Similarly, in C. elegans, geprocessing of meiotic netic studies identified a DSBs, indicating that furregion at one end of each ther steps in recombination chromosome, known as the may also be required for homolog recognition region correct partner choice dur(HRR), which has the proping synapsis or timing of erties that might be expected SC formation (3, 20). of a pairing site (12). These The requirement for sites are able to stabilize DSB formation in synapsis pairing in their vicinity even is not universal. In Droin the presence of mutants sophila females and C. elthat block the formation of the SC (9). A number of re- Fig. 1. During prophase of meiosis I, chromosomes accomplish the three basic steps egans, synapsis occurs norpetitive DNA elements that of pairing, synapsis, and recombination. Interactions between one pair of homolo- mally even in the absence are located within the genet- gous chromosomes (red and blue) within a nucleus during prophase of meiosis are of DSB formation (7, 8). C. ically mapped HRRs were schematically represented. Sister chromatids produced during premeiotic S phase elegans chromosomes enter are shown as different shades of red or blue. Meiotic prophase is classically recently identified, but it is subdivided into five stages: leptotene, zygotene, pachytene, diplotene, and diaki- meiosis unpaired and then not yet known whether the nesis. Chromosomes begin to condense, homologs become aligned along their undergo a rapid alignment. repeats are required for HRR lengths, and AEs form between sister chromatids during leptotene. Zygotene is This alignment requires function (13). Several inter- marked by the initiation of synapsis and building the SC (yellow) between the neither the initiation of renal chromosomal sites that paired homologs. By pachytene, synapsis is completed to produce a mature combination nor the funcmay play a role in facilitat- bivalent. Chiasmata resulting from interhomolog recombination that occurs during tion of proteins that will the zygotene and pachytene stages are evident during the diplotene and diakinesis ing pairing during Drosoph- stages and serve to connect the homologs. Breakdown of the nuclear envelope later facilitate synapsis (9). ila female meiosis have also signals the end of prophase and is followed by formation of the meiosis I spindle Similarly, in Drosophila been defined and mapped to (green). At metaphase I, the pairs of sister kinetochores are attached to the spindle females the existence of regions of intercalary het- and oriented toward opposite poles. Sister chromatid cohesion along the chromo- prior somatic pairing assosome arms is released at anaphase I, and the homologous chromosomes separate ciations may well circumerochromatin (14). vent the need for DSBThe nearly universal ob- and move to the poles (not shown). dependent homology searches. servation of a moderate to are brought into an intimate alignment. SynIt seems likely that the lack of a requiretight clustering of telomeres at the nuclear apsis is defined by the formation of the SC, ment for the creation of recombination inenvelope during the leptotene-to-zygotene which bridges the ⬃100-nm gap between termediates for synapsis in these organisms transition, a configuration known as the homologs (Fig. 2). The SC is comprised of may reflect the ability of flies and worms to “bouquet,” has driven speculation that the two lateral elements (LEs) that are derived use other, DSB-independent means to meprocesses involved in forming the telomere from the axial cores, or axial elements (AEs), diate homolog recognition. However, debouquet may be involved in pairing (15). of meiotic chromosomes. The mature LEs lie spite using a different mechanism to Pairing and synapsis appear to coincide adjacent to chromatin along the length of achieve synapsis, the assembly and strucwith bouquet formation in some systems each chromosome and are connected to each ture of the SC in these organisms are indis(16 ), whereas in others pairing interactions other by transverse filaments. A central eletinguishable from what is observed in DSBoccur well before the bouquet arises and in ment is often observed midway between the dependent synapsis. these cases the bouquet may serve as a lateral elements, running down the central The LEs are derived primarily from the gateway to synapsis (15). Indeed, in both S. portion of the transverse filaments. cohesin complex. The cohesin complex, cerevisiae and S. pombe, mutants have been 8 AUGUST 2003 VOL 301 SCIENCE www.sciencemag.org

THE DYNAMIC CHROMOSOME ize exclusively to the central element. The electron micrograph– defined central element may be a distinct structure composed of proteins yet to be identified, or it could be a region of increased electron density resulting from the overlapping of transverse filament proteins in the center of the SC (Fig. 2). Possible functions for SC. In at least some organisms, the SC serves to hold homologs together during the processes of chromosome compaction and condensation that occur during the transition from leptotene to zygotene (15, 20). In addition, elaborate SC-like structures have been implicated in preserving attachments between homologs that do not undergo exchange,

play an important role in promoting interhomolog exchanges. For example, mutants in the zip1 gene in S. cerevisiae reduce the frequency of recombination by 50 to 70% (27 ). Similarly, mutants in transverse filament protein–encoding genes c(3)G in Drosophila and syp-1 in C. elegans abolish exchange altogether (9, 29). Indeed, a recent study supports the view that DSB formation is reduced by at least fourfold in the absence of the C(3)G protein (40). Several lines of evidence suggest that transverse filament proteins may be capable of interacting with chromatin and influence recombination in an LE-independent manner (23, 41, 42). A second Drosophila SC component, C(2)M, may define a component of the SC required to direct the recombination process into an SCdependent pathway (43). One mechanism by which the SC may mediate interhomolog exchange is through its association with structures referred to as recombination nodules, or RNs. In organisms that possess SCs, sites of recombination are marked along the meiotic chromosomes during pachytene by RNs sitting on top of the SC (Fig. 3) (44, 45). RNs exist in two forms: earFig. 2. SC structure. (Top) General structure of transverse filament ly and late. Considerproteins. The transverse filament proteins identified to date share a able evidence supports common predicted structure that includes a central region rich in the view that early nodcoiled-coils flanked by a largely globular N and C termini (9, 27–29). ules may mark sites of (Bottom) Model of SC structure. During zygotene, LEs (blue) are nonreciprocal meiotic formed from AEs located along homologous chromosomes. Transverse filaments comprised of elongated protein dimers are thought to exchange (gene converinteract with LEs and with each other, possibly forming the central sion), whereas late RNs element as well. The protein constituents (in parentheses) of the LEs mark sites of flanking function both as part of SC structure and to organize chromosomal marker exchange. InDNA in chromatin loops. deed, the number and distribution of late RNs such as in Bombyx mori oocytes (35) and parallels that of reciprocal exchange events the sex chromosomes of Thylamys elegans [for review, see (45)]. A detailed study of (36 ). We can imagine that modifications of protein localization within RNs has demonthe SC play an important role in other strated that these structures contain recomchromosome interactions as well. For exbination proteins and has provided support ample, in Drosophila oocytes the SC for the existence of two distinct types of breaks down at the end of meiotic prophase nodules associated with crossover and nonand the euchromatin desynapses. Nonethecrossover products (46 ). Finally, it is also less, heterochromatic regions remain tightpossible that the SC may serve to mediate ly associated until metaphase and underlie the processes by which exchanges interact the process of achiasmate segregation (37– to control their own distribution, called 39). It might not be unreasonable to imaggenetic interference. Interference is reine that this maintenance of pairing reflects duced in a c(3)G hypomorph and reduced some modification of SC or SC remnants to or eliminated in zip1 mutants, consistent ensure heterochromatic cohesion. with such a possibility (29, 34, 47 ). Second, components of the transverse Meiosis is still possible even in the abfilaments and/or central element may well sence of synapsis. Even though synapsis is

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which mediates sister chromatid cohesion, plays a major role in the assembly of the LEs (21, 22). In yeast, the cohesin proteins Smc3p and Rec8p are associated with SCs during pachytene, and formation of AE fragments or the SC is abolished in mutants that fail to produce these proteins (21). As meiotic prophase progresses in mammalian spermatocytes, REC8 is initially present on short axial structures in the absence of other cohesin components (22). Other cohesin complex proteins, SMC1␤ and SMC3, appear to associate with these REC8-containing AE fragments simultaneously during leptotene (22–24 ). Presumably, the remaining cohesin component, STAG3, also associates with the complex at this time, because this protein also localizes to AEs during prophase I (25, 26 ). Cohesin remains associated with these AE fibers as they coalesce to run along the entire length of the chromosomes at pachytene, suggesting that the cohesins form part of the LEs of the SC. Formation of the transverse filaments. Proteins that form the transverse filaments, which stretch between LEs, have now been identified in several species. These include Zip1p in S. cerevisiae (27 ), SCP1 in mammalian species (28), C(3)G in Drosophila melanogaster (29), and SYP-1 in C. elegans (9). These proteins play similar roles in the construction of the SC, and, although their primary amino acid sequences differ greatly, certain structural characteristics are shared among these proteins (Fig. 2). The most notable common characteristic of these proteins is the presence of an extended coiled-coil rich segment located in the center of the protein, flanked by largely globular domains (9, 27–29). Immunolocalization of SCP1 and Zip1p by electron microscopy has elucidated the organization of these proteins within the SC (30 –33). These results support a model for transverse filaments in which the proteins form parallel dimers through the coiled-coil regions and then align between the chromosomes, with the C termini along the lateral elements. The N termini from opposing dimers interact in an antiparallel fashion down the center of the SC (Fig. 2) (31–34 ). The roles played by the transverse filament proteins remain unclear. One obvious possibility is that they simply connect the LEs. However, several lines of evidence suggest an additional role of this structure in mediating the recombination process (see below). Formation of the central element. Electron micrographs from numerous species suggest the presence of a structural element running down the center of the SC. To date, no proteins have been identified that local-

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observed in most meiotic systems, it is not seen in others (e.g., S. pombe and Aspergillus). Thus, synapsis can be viewed as only one possible outcome of the pairing process. In S. pombe, chromosome pairing proceeds in cells undergoing meiosis, but a canonical SC does not assemble. Instead, discontinuous structures called linear elements form along paired homologs. The linear elements seem to play a role analogous to SC by maintaining pairing interactions and promoting interhomolog recombination (17, 18). S. pombe can nonetheless perform meiotic recombination and reductional segregation of homologous chromosomes in the absence of synapsis. In what is perhaps a similar fashion, mouse oocytes lacking the SC protein SCP3 are often able

Moving the chromosomes to the metaphase plate. The term “congression” refers to the processes that collect the bivalents to the metaphase plate such that the two kinetochores of each bivalent are attached to opposite poles of the spindle (48). At the start of prometaphase, the two homologous centromeres are usually oriented in opposite directions. Thus, most bivalents immediately obtain a bipolar orientation that balances the bivalent on the metaphase plate by virtue of the fact that both kinetochores are being pulled toward opposite poles with an equal force (49). However, some bivalents fail to orient properly, either with both kinetochores attached to the same pole or with only one kinetochore attached to a pole. In this case, the kinetochores are able

point genes lead to high frequencies of chromosome nondisjunction at anaphase I (52). There is a much stronger system for error detection in male meiosis that detects misaligned or unpaired chromosomes before the first meiotic division and, having done so, directs the cell toward death (53). Although oocytes appear to lack such a tension-sensitive checkpoint (54 ), at least some workers have proposed that agedependent defects in the ability of oocytes to monitor at least some aspects of spindle assembly and/or chromosome position may well be a factor in the maternal effect on meiotic nondisjunction in humans (52). Connecting two sister kinetochores to one spindle pole: monopolar attachment. To guide homologous chromosomes to opposite poles during meiosis I, each pair of sister kinetochores must function as a single unit, establishing an attachment to the same pole. Recent work has identified a group of S. cerevisiae proteins, termed “monopolins,” that are required for monopolar attachment at meiosis I and has begun to elucidate how this process is regulated (55, 56 ). These proteins— Mam1p, Csm1p, and Lrs4 — are required for the first meiotic division. In meiotic cells depleted for monopolins, homologs fail to segregate, despite normal recombination and regulation of sister chromatid cohesion, because sister kinetochores attain bipolar Fig. 3. The role of sister chromatid cohesion in meiosis. Cohesion complex proteins deposited along chromosomes (red and blue) during premeiotic S phase ensure sister chromatid cohesion and are necessary for the formation of microtubule attachments that the SC. This facilitates the formation of interhomolog exchanges during pachytene, which are evident as chiasmata. are resisted by Rec8p-mediatCohesion between sister chromatid arms maintains the chiasmata, which keep the two homologs connected up to ed cohesion between sister and during metaphase I. In S. cerevisiae, the monopolins bind to centromeres and facilitate monopolar kinetochore chromatids. In the wild type, orientation at metaphase I (55, 56). Homolog segregation at anaphase I is made possible by the release of cohesion the monopolins are essential along chromatid arms, whereas cohesion at the centromere is protected from release until anaphase II. for ensuring that each pair of sister kinetochores establishto complete oogenesis and support levels of to go through successive cycles of microes a monopolar spindle attachment, resultmeiotic recombination close to those of the tubule release and reattachment until stable ing in the reductional division of homologs wild type without the formation of a normal bipolar orientation is established. Errors in at anaphase I (55, 56 ). SC (42). the progress of chromosome congression Sister chromatid cohesion ensures chiare known to be more common in older asma function. Chiasmata, the physical Turnout: Chromosome Segregation oocytes (50), and the first true mammalian manifestation of reciprocal meiotic exAt the end of meiotic prophase, chromoaneuploidy-inducing compound to be dischange, lock the homologs together (57 ). somes begin the process of aligning themcovered, bisphenol A, acts by impeding this Once the two homologous centromeres are selves on or, in the case of most female process (51). attached to opposite poles of the meiotic meiotic systems, constructing the spindle Many meiotic systems possess checkspindle, the chiasmata prevent premature on which the first meiotic division will take point or surveillance mechanisms to ensure progression of the centromeres to the poles place. There are three basic components to that chromosomes are attached to the propby balancing the poleward forces localized this process: (i) congression of chromoer poles, as assessed by the presence of mainly at the kinetochore (Fig. 3). Sister somes to the metaphase plate, (ii) aligntension on the kinetochores. An improperly chromatid cohesion distal to crossovers ment of all chromosomes on that plate, and attached kinetochore, or pair of kinetomaintains chiasmata at their initial posi(iii) the separation of homologous chromochores, will not be under tension and thus tions until anaphase I (58). For example, somes to opposite poles at the first meiotic trigger a meiotic arrest, or even apoptosis. mutants of the desynaptic gene in maize division. Moreover, mutations in the spindle checkdisplay both precocious sister chromatid 8 AUGUST 2003 VOL 301 SCIENCE www.sciencemag.org

THE DYNAMIC CHROMOSOME protect centromeric Rec8p from separasemediated cleavage but cannot protect other separase substrates (21, 68, 69). Pulling the chromosomes apart. The final step in executing the first meiotic division is the actual movement of homologous chromosomes to opposite poles, both by mechanisms in which motor molecules at the kinetochore pull the chromosomes to the poles and by mechanisms that actually push the two poles apart from each other. Although mechanisms of spindle elongation and kinetochore-based movement lie outside the scope of this review, these processes have been thoroughly discussed in several recent reviews (70 –72).

Summary Although many aspects of the meiotic process are now much better understood than they were even a decade ago, many aspects of the process remain obscure. Perhaps the most notable of these is the mechanism(s) by which initial pairing is achieved. This process, which embodies the fundamental biological problem of telling “self from nonself,” remains enigmatic. We are similarly uncertain with respect to the mechanisms by which exchange distributions are established or how it is determined whether or not a given DSB will result in flanking marker exchange. Finally, despite its intriguing and conserved structure, the SC remains the “elephant in the meiotic living room.” We know it is there, we know something of its dimensions, but its “reason for being” remains a matter of some conjecture. It seems likely, though, that better techniques and better mutants will soon shed light on even these most vexing questions. References and Notes

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separation, suggesting a defect in sister centromere cohesion, and the early separation of chiasmate bivalents (59). In Drosophila, chiasmata fail to conjoin homologous chromosomes in the presence of mutations at the ord locus, which disrupt sister chromatid cohesion during meiotic prophase (60). Similarly, in yeast the cleavage of Rec8p, a protein required for meiotic sister chromatid cohesion, is required for chiasma resolution, and homolog separation is blocked in the absence of this cleavage (61). Chiasmata are not positioned randomly along chromosome arms, but rather tend to cluster in the middle of the arms. Exchanges too distal will not provide sufficient sister chromatid cohesion to ensure segregation; events too proximal will not be resolvable, given the need of the cell to maintain sister chromatid cohesion near the centromeres until anaphase II (62). The release of sister chromatid cohesion distal to chiasmata allows homologs to separate. In mitotic cells, separase is necessary for the proteolytic cleavage of cohesin around the centromere (and both centromeres and arms in yeast), allowing chromosome segregation at anaphase (63, 64). In a similar manner, cleavage of cohesin by separase is also necessary for chromosome segregation during anaphase I (61, 65). Although arm cohesion must be maintained through prophase in order to maintain chiasmata, the release of cohesion is essential to allow the segregation of homologs to opposite poles at anaphase I. However, this creates a “Catch-22” situation: Dissolution of sister chromatid cohesion in the arms would release the chiasmata that hold the homologs together, yet the centromeres of sister chromatids have to remain together to ensure that the homologs segregate correctly and prevent sister chromatid missegregation. Maintenance of cohesion at the centromeres and release of sister chromatid cohesion along the arms is achieved through the differential removal of cohesins from the arms and centromeres of the chromosomes. Immunolocalization of cohesin components during mammalian meiosis indicates that the cohesin complex is removed from chromosome arms at metaphase I but retained at the centromere until the second meiotic division (22, 24, 26 ). Maintenance of cohesin at the centromeres depends on the presence of the meiosis-specific Scc1p homolog Rec8p, which replaces Scc1p in the meiotic cohesin complex in most systems (21, 22, 66, 67 ). Scc1p is sufficient for sister chromatid cohesion in yeast meiosis in the absence of Rec8p but is not protected from cleavage at the first meiotic division (55). Yeast Spo13p is necessary and sufficient to

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