INSIGHTS | PERSPECTIVES
SUMO E3 ligases, the restriction of RNF212
to crossover sites depends on the proposed
function of human enhancer of invasion 10
(HEI10) as an E3 ubiquitin ligase that recognizes SUMOylated proteins and targets them
for destruction (8). Given that SUMO modification can stabilize targets, yet at the same
time reveal them to the proteolytic machinery, the functional pairing of RNF212 and
HEI10 in crossover formation sets in place a
potential “race” between SUMO stabilization
of a crossover-competent intermediate for
crossover formation, and destabilization and
noncrossover formation through protease-mediated degradation (see the figure).
To investigate the inferred protein activities of RNF212 and HEI10 in vivo, Prasada
Rao et al. examined SUMO, ubiquitin, and
proteasome localization in individual mouse
mutants lacking either putative E3 ligase.
The authors indeed found correlations con-
sistent with a “race” model. Nevertheless,
HEI10-dependent removal at others. How-
ever, not all organisms require the functions
of both RNF212 and HEI10. Budding yeast
lack an obvious HEI10-like protein, whereas
plants (10, 11) and Sordaria fungi (12) lack an
RNF212 counterpart and instead rely on a
single HEI10 ortholog for crossover forma-
tion. Furthermore, Sordaria Hei10 incorpo-
rates functional characteristics of the mouse
RNF212-HEI10 relay in that it mediates both
the acquisition and depletion of SUMOylated
chromosomal targets (12). These studies col-
lectively suggest that the effectors of the
SUMOylation and ubiquitylation pathways
in different organisms may vary in number
and biochemical competencies while nego-
tiating the formation of mature crossovers.
Using the generous experimental tools of
budding yeast, Ahuja et al. also identified a
role for the proteasome in an earlier event
in the crossover pathway—bringing the two
chromosome homologs together in the first
place to exchange their DNA. Although the
molecular details of homolog recognition
and chromosome pairing remain poorly
understood, an emerging model is that the
physical restriction of certain chromosome
regions within the spatial confines of the
nucleus promotes homolog engagement.
For example, a widely adopted tactic is the
tethering of telomeres of meiotic chromo-
somes to the nuclear envelope and restrict-
ing them to a small space (13). Another event
in many species is the physical coupling of
centromeres, which precedes pairing of chro-
mosomal arms (14). In yeast, these centro-
mere interactions require the synaptonemal
complex component Zip1. Because synapto-
nemal complex proteins can assemble be-
tween nonhomologous sequences, they must
be removed from nonhomologously paired
centromeres to enable productive homolo-
gous pairing interactions. In the absence of
a functional yeast proteasome, chromosomes
display profound defects in pairing and allow
centromere interactions between nonhomo-
logs to inappropriately persist, and conse-
quently disrupt homologous pairing.
Protein degradation has well-known roles
in regulating meiotic chromosome segregation. The E3 ligase anaphase-promoting complex (APC) mediates degradation of securin.
Securin inhibits separase, an enzyme that
cleaves the cohesion complex. Thus, APC activity leads to the liberation of chromosomes
for segregation (15). It is now evident from
the work of Prasada Rao et al. and Ahuja et al.
that the proteasome is also required for earlier events at chromosomes during prophase
of meiosis I that facilitate the crossovers required for accurate chromosome segregation.
Although the direct targets of the E3 ligases
implicated in these studies are still unknown,
our understanding of meiotic prophase transitions has been elaborated by the inclusion
of timely protein stabilization and degradation as regulatory mechanisms. j
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of meiosis I
to fnd their homologs
Stable site destined
Race to recombination
The model shows how SUMO modification may stabilize crossover sites between homologous chromosomes,
but also makes these crossover-competent sites visible to the proteasome. Sites that are further ubiquitylated
could become destabilized through protease-mediated degradation and are repaired as noncrossovers.