Download Chromosome Choreography: The Meiotic Ballet

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).
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(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).
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34. E. J. Harry, Mol. Microbiol. 40, 795-803 (2001).
35. K. Gerdes, J. Moller-Jensen, R. B. Jensen, Mol. Microbiol. 37, 455 (2000).
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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
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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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SPECIAL SECTION
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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SPECIAL SECTION
THE DYNAMIC CHROMOSOME
788
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
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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.
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we apologize to those authors whose work we did
not have space to include.
www.sciencemag.org SCIENCE VOL 301 8 AUGUST 2003
SPECIAL SECTION
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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