Growth, Differentiation and Sexuality

A. Chromosome
and Sister-Chromatid Segregation
Are Mediated
by the Cohesin Complex
Proper sister-chromatid cohesion is a fundamental
aspect of chromosome segregation. Both in mitosis
and meiosis, cohesion is mediated by evolutionarily
conserved chromosomal proteins, termed “cohesins”.
The cohesin complex consists of two long,
coiled-coil proteins, Smc1 and Smc3, and two regulatory
subunits called Scc1/Mcd1/Rad21 and Scc3.
All members of the complex are essential for cohesion,
since mutations result in precocious separation
of sister chromatids (review in Nasmyth 2001).
Several lines of evidence suggest that cohesins are
loaded onto chromosomes during or immediately
following S-phase in meiosis as in mitosis. They
are removed by proteolysis of the Scc1/Rad21 subunit
at anaphase onset, which in turn is thought
to trigger chromatid separation (review in Nasmyth
2001). Chromatin immunoprecipitation analyses
along budding yeast chromosomes show that
cohesins tend to associate with AT-rich regions,
and an even higher enrichment is seen in the pericentric
region. This pattern of sites is very similar
in mitotic and meiotic cells (review in Glynn
et al. 2004). A negative correlation is found between
the location of meiotic cohesins and that
of the DSBs that initiate meiotic recombination:
DSBs tend to occur in GC-rich regions where cohesins
are absent, and cohesins tend to be located
in regions that contain low levels of DSBs (Glynn
et al. 2004). Cohesins function not only in chromosome
segregation but also in DNA repair by
homologous recombination (review in Jessberger
2002).
At least three cohesin subunits have meiosisspecific
variants. Rec8 replaces largely Scc1/Rad21
in all species analyzed so far (e.g., Klein et al. 1999;
Watanabe and Nurse 1999). The ability of meiotic
centromeric cohesion to resist the endopeptidase
Esp1 (called separase) requires Rec8: when Scc1
is expressed instead of Rec8 during meiosis, cohesion
is destroyed in both arm and centromere
at metaphase I (Buonomo et al. 2000). In fission
yeast, both Rec8 and Rad21 are present, but show
distinct localization patterns in the centromeric region,
and determine the manner of kinetochore attachment
to microtubules (Yokobayashi et al. 2003).
Scc3 is partially replaced by Rec11/STAG3, along
arms but not at centromeres (Prieto et al. 2001).
Mammalian spermatocytes also express a meiosis-
Fungal Meiosis 429
specific version of SMC1, called SMC1β (Revenkova
et al. 2004). Requirement for meiosis-specific cohesins
is a clear indication of a reinforcement of
their functions during meiosis (review in Nasmyth
2001).
Cohesins have at least four meiotic functions,
as shown by the fact that cohesin mutants have
multiple phenotypes.
1. They are required for the regulation of DSB
repair. In the absence of REC8, SMC3 or SCC3,
DSBs are normally formed but not properly
repaired, as seen by the accumulation of Rad51
foci, severely reduced recombination, and
from the presence of broken chromosomes at
diplotene (Klein et al. 1999; Pasierbek et al.
2001, 2003).
2. The cohesin complex stabilizes chiasmata
along chromosome arms: cleavage of Rec8 is
needed for homologue segregation only if they
are joined by chiasmata (Buonomo et al. 2000).
3. Cohesins co-localize with SC axial elements
(AEs) and are implied in SC assembly (Klein
et al. 1999; Pelttari et al. 2001; Eijpe et al. 2003;
Revenkova et al. 2004 and references therein).
First, SCs are not formed in the absence of either
Rec8 or Scc3 (Klein et al. 1999; Pasierbek
et al. 2003). Second, the cohesin core provides
a scaffold for binding both AE and recombination
proteins. The central region protein SCP1
forms SCs in the absence of the AE components
SCP3 and SCP2, showing that the organization
of the cohesin complex is sufficient for
SCP1 fixation to the chromosome axes (Pelttari
et al. 2001). Third, co-immunoprecipitation experiments
suggest a physical association between
cohesins and both SCP2 and SCP3 (Eijpe
et al. 2000). Fourth, reciprocally, AE componentsappeartoberequiredtoreinforcesisterchromatid
cohesion: mutations in genes encoding
AE components cause premature separation
of the sister chromatids during meiosis
I in budding yeast and C. elegans (review in
Lee and Orr-Weaver 2001; Eijpe et al. 2003).
Also, the persistent localization of AE proteins
along arms up to the anaphase I onset strongly
suggests a role in sister cohesion (Eijpe et al.
2003).
4. The meiosis-specific cohesin SMC1β is also
required for orderly chromosome processing:
AEs and SCs are shorter, and chromosome
loops are enlarged in the absence of SMC1β
(Revenkova et al. 2004).