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Current Biology, Vol. 14, R834–R836, October 5, 2004, ©2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.cub.2004.09.035
Dispatch
Adherin: Key to the Cohesin Ring and
Cornelia de Lange Syndrome
Dale Dorsett
Adherin facilitates sister chromatid cohesion, DNA
repair and binding of the cohesin complex to
chromosomes. New studies indicate that adherin
activity is coordinated with DNA replication and chromosome segregation, and that its dosage is critical
for gene expression and human development.
A recent flurry of papers provides new insights into
how the adherin proteins (Table 1) regulate diverse
chromosomal functions and development. Adherin
functions were originally revealed by genetic mutations
in fungi: the rad9-1 adherin mutant of the mushroom
Coprinus cinereus is defective in meiotic DNA repair,
chromatid cohesin and homolog pairing [1]; mis4
adherin mutants of the fission yeast Schizosaccharomyces pombe display DNA repair and mitotic sister
chromatid cohesion defects [2]; and scc2 adherin
mutations in the budding yeast Saccharomyces cerevisiae disrupt mitotic chromatid cohesion [3].
A number of new papers report evidence that the
chromosome cohesion function of adherin is
conserved in higher organisms. Rollins et al. [4] found
Drosophila Nipped-B adherin mutations, which reduce
transcriptional activation of homeotic genes by distant
enhancer sequences [5], also cause cohesion defects.
Gillespie and Hirano [6] have shown that depletion of
both isoforms of the Xenopus adherin XScc2 from egg
extracts blocks cohesion. And in a dramatic development, Krantz et al. [7] and Tonkin et al. [8] report that
human NIPBL adherin mutations cause Cornelia de
Lange syndrome, which affects many aspects of
physical and mental growth.
The adherins of different organisms are homologous
and contain several HEAT repeats, protein interaction
motifs which are conserved in spacing and position [9].
A key question is whether the diverse roles of adherins
in cohesion, DNA repair, gene expression and development reflect a single function, or multiple different
mechanisms. The known adherin function is to facilitate chromosomal binding of the cohesin protein
complex that holds sister chromatids together [10,11].
Cohesin is one of many ‘structural maintenance of
chromosome’ (SMC) complexes, conserved in overall
structure from bacteria to man, which play diverse
roles in chromosome architecture and function
(reviewed in [12]). Cohesin consists of Smc1, Smc3,
Rad21 (Mcd1/Scc1) and Scc3 (Stromalin) subunits
(Figure 1). Smc1 and Smc3 interact to form a V-like
structure with two ATPase head domains, and Rad21
interacts with both ATPase domains to form a ring-like
Edward A. Doisy Department of Biochemistry and Molecular
Biology, Saint Louis University School of Medicine, Saint
Louis, Missouri 63104, USA.
structure. In budding yeast, cohesin binds every
10 kilobases or so along the chromosomes, preferring
regions between convergent transcription units [13,14].
An attractive model for cohesion is that the cohesin
ring encircles DNA so that subsequent replication
captures the two sister chromatids within the ring [15]
(Figure 1). Other possibilities include a ‘snap’ model in
which two cohesin rings bound to the two sister chromatids loop through each other [16]. In either case,
establishing cohesion requires opening of the cohesin
ring. ATP hydrolysis mutations in the cohesin ATPase
domains and scc2 adherin mutations have the same
effect: cohesin rings form but fail to bind to chromosomes [17,18]. This raises the idea that adherins stimulate ATP hydrolysis and ring opening [17] (Figure 1).
Small amounts of cohesin subunits co-purify with the
Scc2/Scc4 adherin complex, indicating that adherin
acts directly on cohesin [17]. Recent chromatin
immunoprecipitation experiments with scc2 mutants
by Lengronne et al. [14] support this idea, because
they indicate that cohesin loads at adherin binding
sites and translocates away (Figure 1).
Recent experiments with Xenopus egg extracts by
Gillespie and Hirano [6] and Takahashi et al. [19]
indicate that binding of adherins to chromosomes is
regulated to coordinate sister chromatid cohesion and
DNA replication (Figure 1). Both groups found that
geminin inhibition of Cdt1, an essential component of
the pre-replication complex that binds origins of DNA
replication, reduced chromosomal association of the
XScc2 adherin and cohesin. Moreover, depletion of
the XOrc1 component of the origin recognition
complex [6,19] or the Mcm2–7 complex that licenses
origins [19], also blocked adherin binding. In contrast,
blocking initiation of DNA replication or origin unwinding with p21CIP1 [6] or p27Kip [19] had no detectable
effect on binding of adherin and cohesin to chromatin.
Dissociation of adherin from chromatin in prophase
was blocked by depletion of the cdc2 mitotic kinase,
while depletion of polo-like and aurora B kinases,
required for prophase dissociation of cohesin, had no
effect on adherin binding [6]. It remains to be seen if
the protein complexes that bind to replication origins
Table 1. Adherins and their functions.
Organism
Adherin
Demonstrated functions
C. cinereus
Rad9
Meiotic DNA repair,
chromatid cohesion, homolog pairing
S. pombe
Mis4
Mitotic sister chromatid cohesion,
DNA repair
S. cerevisiae
Scc2
Mitotic sister chromatid cohesion
Drosophila
Nipped-B Long-range gene activation, sister
chromatid cohesion
Xenopus
XScc2A,B Mitotic sister chromatid cohesion
H. sapiens
NIPBL-A,B Physical and mental development
Current Biology
R835
Figure 1. Proposed mechanisms for
binding of adherin and cohesin to chromosomes.
Recent work indicates that licensing of
DNA replication origins, which involves
binding of the origin recognition complex
(ORC), Cdt1, and the Mcm2–7 complex,
stimulates chromosomal binding of
adherin by an unknown mechanism
[6,19]. Adherin is proposed to stimulate
ATP hydrolysis and opening of the
cohesin ring to facilitate entry of the
chromosome into the cohesin ring [17].
Subsequent DNA replication would trap
both sister chromatids in the cohesin
ring. From the opposing effects of
adherin and cohesin on gene expression,
it is proposed that adherin also facilitates
localized or temporary removal of
cohesin to allow long-range gene activation [4]. Prophase removal of adherin
from chromosomes is stimulated by cdc2
mitotic kinase, but not by polo-like kinase
or aurora B kinase, which are required for
prophase cohesin removal [6].
Mcm2-7
Replication origin licensing
adherin binding
Adherin
ORC
Cdt1
Cohesin
Rad21/Mcd1/Scc1
Stromalin/Scc3
ADP+Pi
Smc1+Smc3
ATP
Cohesin loading
DNA replication
ADP+Pi
Localized cohesin removal
gene activation
Prophase adherin and
cohesin removal
Polo-like kinase
aurora B
ATP
Cdc2
Current Biology
directly recruit adherin, or if formation of originbinding complexes initiates a signal that alters the
ability of adherin to bind to chromatin.
In addition to sister chromatid cohesion, chromosomal loading of cohesin by adherins can also explain
their role in DNA repair. Human cohesin is recruited to
sites of DNA damage, and this recruitment depends
on Mre11, a critical component of a complex that
binds chromosome breaks and is required for recombination and repair [20]. The mushroom adherin Rad9
functions in an Mre11-dependent repair pathway [1].
So beyond fulfilling a basic requirement for chromatid
juxtaposition for repair, it seems likely that adherins
load additional cohesin at DNA damage sites.
The recent experiments by Rollins et al. [4] raise the
possibility that adherin may remove cohesin from
chromosomes to facilitate gene expression. The
Drosophila adherin Nipped-B facilitates long-range
activation of the cut and Ultrabithorax homeotic genes
by distant transcriptional enhancers in a dosagesensitive manner [5]. Partial reduction of Nipped-B
function reduces activation of these genes, while
complete loss of Nipped-B function causes cohesion
defects [4,5]. Surprisingly, Nipped-B and cohesin have
opposing effects on gene expression, and partial
reduction of cohesin subunits increased cut activation
without causing cohesion defects [4].
This dichotomy can be explained if cohesin blocks
enhancer–promoter interactions, and Nipped-B facilitates activation by removing cohesin. If adherin opens
the cohesin ring, this could aid both cohesin loading
and removal of cohesin from chromosomes (Figure 1).
There may be a steady state between chromosomal
and extra-chromosomal cohesin, with the adherin
level determining the on–off rates and opportunities
for gene activation. It is also possible, however, that
cohesin inhibits gene expression by preventing
adherin from performing another task that supports
activation.
Dissecting the roles of adherin and cohesin in gene
activation will be critical for understanding Cornelia de
Lange syndrome, which displays a variety of developmental deficiencies, including growth, upper limb,
cardiac, gastroesophageal and learning defects.
Dispatch
R836
Krantz et al. [7] and Tonkin et al. [8] showed that this
syndrome, which occurs as frequently as once per
10,000 births, is caused by spontaneous loss-offunction mutations in one copy of the human NIPBL
adherin gene. Because the developmental symptoms
are caused by reduced adherin dosage, they likely
reflect gene expression changes as opposed to
cohesion or repair defects. Indeed, effects on
homeotic gene expression similar to those caused by
partial loss of Drosophila adherin might explain many
features of Cornelia de Lange syndrome, such as
upper limb abnormalities.
The Xenopus egg studies by Gillespie and Hirano [6]
and Takahashi et al. [19] show that the binding and
removal of adherin to and from chromosomes are
coordinated with replication origin licensing and
mitotic entry, which ensures that cohesion and loss of
cohesion are properly synchronized with DNA replication and chromosome segregation. This also means,
however, that cohesin is bound to chromosomes
throughout interphase. Given the sensitivity of
homeotic gene expression to small changes in adherin
and cohesin dosage, and the devastating developmental consequences of such changes as evidenced
by Cornelia de Lange syndrome, it seems likely that
additional mechanisms are needed to fine tune interphase adherin and cohesin activity.
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