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1.
Nasmyth K 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2005,360(1455):483-496
The sister chromatid cohesion essential for the bi-orientation of chromosomes on mitotic spindles depends on a multi-subunit complex called cohesin. This paper reviews the evidence that cohesin is directly responsible for holding sister DNAs together and considers how it might perform this function in the light of recent data on its structure. 相似文献
2.
The cohesin complex is proposed to embrace sister chromatids within its ring-like structure, in which two ATP-binding 'head' domains of an SMC (structural maintenance of chromosomes) heterodimer are linked by a kleisin subunit. Recent studies shed new light on the crucial functions of the 'hinge' domain of the SMC dimer, which is located approximately 50 nm from the head domains. An emerging idea is that the hinge and head domains cooperatively modulate cohesin-DNA interactions by opening and closing the ring in a highly regulated manner. 相似文献
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4.
Peters JM 《The EMBO journal》2012,31(9):2061-2063
EMBO J
31
9, 2076–2089
March132012EMBO J
31
9, 2090–2102
March132012It is well known that somatic and germ cells use different cohesin complexes to
mediate sister chromatid cohesion, but why different isoforms of cohesin also
co-exist within somatic vertebrate cells has remained a mystery. Two papers in this
issue of The EMBO Journal have begun to address this question by analysing
mouse cells lacking SA1, an isoform of a specific cohesin subunit.When one cell divides into two, many things have to go right for the two daughter cells
to receive identical copies of their mother cell''s genome. It has long been
recognized that sister chromatid cohesion, the physical connection established during
DNA replication between newly synthesized sister DNA molecules, is one of these
essential prerequisites for proper chromosome segregation. It is this cohesion that
enables the bi-orientation of chromosomes on the mitotic or meiotic spindle, and thus
makes their symmetrical segregation possible. Cohesion is mediated by cohesin, a
multi-subunit protein complex, which is thought to connect sister DNA molecules by
embracing them as a ring (Figure 1; reviewed in Peters et al, 2008). It is well established that cohesin complexes
differ between somatic and germ cells, where they are needed for the proper separation
of sister chromatids and of homologous chromosomes, respectively. What has been largely
ignored, however, is that even within somatic vertebrate cells there are different forms
of cohesin, containing mutually exclusive variable subunits: either SA1 or the closely
related SA2 protein (also known as STAG1 and STAG2, respectively), and either Pds5A or
the related Pds5B subunit (Peters et al, 2008). Why
is that? Two papers from the Losada lab (Remeseiro et al,
2012a, 2012b) have begun to address this
question by generating mouse cells lacking the SA1 gene, revealing unexpected
insights into the functions of SA1 subunit-containing cohesin complexes
(cohesin-SA1).Open in a separate windowFigure 1Schematic drawing illustrating how the SA1 and SA2 proteins interact in a
mutually exclusive manner with three core subunits of cohesin (Smc1, Smc3,
Rad21) that form a ring-like structure. It has been proposed that these
complexes mediate cohesion by trapping the two sister DNA molecules inside
the cohesin ring (above), and that cohesin rings might affect chromatin
structure by forming or stabilizing intra-chromatid loops (below). Cohesin
is thought to influence gene regulation at least in part by mediating
chromatin looping.Although cohesin is best known for its role in sister chromatid cohesion, it is clearly
also needed for homologous recombination-mediated DNA repair and for gene regulation.
Much of what we know about these functions comes from studies in yeast and fruit flies,
organisms with only a single SA1/SA2-related mitotic subunit (Scc3 in budding yeast),
and only a single Pds5 subunit. It is therefore plausible that, like many other genes
during vertebrate evolution, SA1/SA2 and Pds5A/Pds5B have arisen by gene duplication to
constitute paralogs, with functional differences between them assumed to be subtle.
Consistently, absence of either Pds5A or Pds5B causes only mild, if any, defects in
sister chromatid cohesion, and mice lacking either protein can develop to term, although
they die shortly after birth owing to multiple organ defects (Zhang
et al, 2007, 2009). First
indications that the situation may be different for the Scc3-related subunits came from
Canudas and Smith (2009), who reported that RNAi
depletion of SA1 and SA2 from HeLa cells caused defects in telomere and centromere
cohesion, respectively. The generation of mice lacking either one or both alleles of the
SA1 gene has now allowed a more systematic and thorough analysis of SA1
function (Remeseiro et al, 2012a, 2012b).One of the most striking results obtained in these studies is that most mice lacking SA1
die around day 12 of embryonic development, clearly showing that the function of SA1
cannot be fulfilled by SA2, despite the fact that SA2 is substantially more abundant in
somatic cells than SA1 (Holzmann et al, 2010). What
could this SA1-specific function be? Losada and colleagues report observations, which
imply that SA1 does not have just one, but possibly several important functions in
different processes. First, the authors confirm the previous observation that SA1 is
required for cohesion specifically at telomeres, while likely collaborating with SA2 in
chromosome arms or centromeric regions. Furthermore, telomeres have an unusual
morphology in mitotic chromosomes lacking SA1 (Remeseiro et al,
2012a), reminiscent of a fragile-site phenotype previously reported in
telomeres with DNA replication defects (Sfeir et al,
2009), and SA1 is indeed required for efficient telomere duplication.
Depletion of sororin, a protein that is required for cohesin''s ability to mediate
sister chromatid cohesion, also causes a fragile-site phenotype at telomeres. These
findings imply that SA1''s role in telomere cohesion is important for efficient
telomere replication, perhaps, as the authors speculate, because telomere cohesion may
help to stabilize or re-start stalled replication forks, or because cohesion-dependent
homologous recombination might be involved in repair of DNA double strand breaks created
by collapsed replication forks. Interestingly, cells lacking SA1 frequently show
chromosome bridges in anaphase, often fail to divide, and either die or become
bi-nucleated. The exact origin of chromosome bridges is difficult to determine, but
previous studies have found such bridges often associated with fragile sites on
chromosomes; treatment with low doses of DNA replication inhibitors was shown to
increase the frequency of such bridges (Chan et al,
2009), and similar observations were indeed made by Remeseiro et al (2012a) in mouse embryonic fibroblasts. It is
therefore plausible that the telomere cohesion defect observed in SA1-lacking cells
leads to incomplete telomere replication, which in turn results in the formation of
anaphase chromosome bridges and subsequent cytokinesis defects. Losada and colleagues
further speculate that these chromosome segregation defects could underlie the increased
frequency of spontaneous development of various tumours in mice containing just one
instead of two SA1 alleles (Remeseiro et al, 2012a).
This is an attractive interpretation since tetraploidy and aneuploidy are thought to
contribute to the rate with which tumour cells can evolve; however, Losada and
colleagues report SA1 deficiency to cause defects also in other cohesin functions, which
may therefore as well contribute to tumour formation.To further understand why SA1 cannot be fulfilled by SA2, Losada and colleagues also
analysed the distribution of these proteins in the non-repetitive parts of the mouse
genome by chromatin immunoprecipitation coupled to deep sequencing (ChIP-seq). The
results of these experiments, published in the second of the two papers (Remeseiro et al, 2012b), raise the interesting possibility
that cohesin-SA1 associates more frequently with gene promoters than cohesin-SA2.
However, the fact that different antibodies have to be used for any ChIP-based
comparison of the distribution of two proteins makes it difficult to know to what degree
observed differences might be due to different antibody efficiency. Obviously, such
limitations do not exist if the distribution of one and the same protein is analysed
under different conditions, and in such an experimental setting, Remeseiro et al
indeed make some striking observations. When SA1 is absent, SA2 does not detectably
change in abundance, but its distribution in the genome does, in that more than half of
all SA2-binding sites in SA1-deficient cells differ from those bound in wild-type cells.
Most SA2-binding sites in SA1-deficient cells are in intergenic regions, and CTCF, a
zinc finger protein often co-localizing with cohesin and implicated in its gene
regulation function (Peters et al, 2008), appears to
be absent at many of these sites. It presently remains a mystery why cohesin-SA2 changes
its distribution so dramatically in the absence of SA1, but the observation that gene
promoters are more frequently occupied by cohesin in the presence of SA1 than in its
absence raises the possibility that cohesin-SA1 may have a specific role in gene
regulation. This possibility is particularly interesting in light of a recent study that
found hardly any change in gene expression upon re-expression of SA2 in SA2-deficient
human glioblastoma cells (Solomon et al, 2011),
despite the fact that cohesin is thought to regulate numerous genes. With this in mind,
Remeseiro et al analysed gene expression in mouse cells and indeed found 549
genes to be mis-regulated in the absence of SA1, in striking contrast to the
above-mentioned comparison of human SA2-deficient or proficient cells that found only 19
genes to change in expression levels (Solomon et al,
2011). Obviously direct comparisons will be essential to analyse further
the specific roles of SA1 and SA2 in gene regulation, but the current evidence raises
the interesting possibility that SA1 may have a particularly important role in gene
regulation, whereas cohesin-SA2 is dedicated to creating arm and centromeric cohesive
structures for chromosome segregation.That is not to say that cohesin-SA1 cannot mediate sister chromatid cohesion. It almost
certainly can, as it is essential for cohesion at telomeres (Canudas
and Smith, 2009; Remeseiro et al,
2012a). Likewise, it would be wrong to assume that we now fully understand why
SA1 and SA2 co-exist in somatic vertebrate cells, and what their precise functions is.
There are many things we do not understand. For example, if SA2 has little or no role in
gene regulation, as the Solomon et al (2011) study
implies, why does SA2 nevertheless interact directly with CTCF (Xiao
et al, 2011), its gene regulation collaborator? How do
cohesin-SA1 and cohesin-SA2 complexes further differ in their genomic distributions and
their functions depending on whether they contain either Pds5A or Pds5B, constituting
really not just two but four distinct cohesin complexes? The work by Losada and
colleagues represents an important step towards understanding these questions, but there
is still a long and presumably exciting way to go to understand how different cohesin
complexes control the mammalian genome. 相似文献
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《中国科学:生命科学》2015,(8)
位于人体不同部位的成纤维细胞具有细胞特异性的HOX基因表达模式,可以作为区分不同成纤维细胞的依据之一.在个体发育的过程中,建立或维持不同HOX基因表达模式的机制始终是引人关注的问题.本实验室前期工作在NT2/D1人畸胎瘤细胞中证明了CTCF/cohesin介导的染色质高级构象在维甲酸诱导的HOXA基因共线性开启过程中发挥了重要作用.为了进一步研究原代细胞中CTCF/cohesin对HOXA基因的调控作用,本研究选取了来自体轴不同部位并且HOXA基因表达模式互补的人胚肺和包皮成纤维细胞,对HOXA基因簇中CTCF和cohesin的结合水平以及相关的染色质高级构象进行了检测.与人胚肺成纤维细胞相比,包皮成纤维细胞中的cohesin结合水平较低,相关的染色质高级构象比较"开放",并且主要表达5′端的HOXA基因.本研究还发现CTCF结合位点CBSA56处于HOXA基因簇染色质高级构象中的核心位置,并且该位点参与的染色质相互作用在两种成纤维细胞中呈现出明显的差异,说明CBSA56是一个关键的CTCF结合位点.以上结果表明,CTCF和cohesin参与了人原代成纤维细胞中HOXA基因簇染色质高级构象的组织和HOXA基因的表达调控,并且提示细胞类型特异性的染色质高级构象与HOXA基因的空间共线性表达模式之间存在协同关系. 相似文献
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10.
《Biocatalysis and Biotransformation》2013,31(3):309-315
Cellulosomes are highly elaborate multi-enzyme complexes of Carbohydrate Active enZYmes (CAZYmes) secreted by cellulolytic microorganisms, which very effectively degrade the most abundant polymers on Earth, cellulose and hemicelluloses. Cellulosome assembly requires that a non-catalytic dockerin module found in cellulosomal enzymes binds to one of the various cohesin domains located in a large molecular scaffold called Scaffoldin. A diversity of cohesin–dockerin binding specificities have been described, the combination of which may result in complex plant cell wall degrading systems, maximising the synergy between enzymes in order to improve catalytic efficiency. Structural studies have allowed the spatial flexibility inherent to the cellulosomal system to be determined. Recent progress achieved from the study of the fundamental cohesin and dockerin units involved in cellulosome assembly will be reviewed. 相似文献
11.
Jekaterina Erenpreisa Kristine Salmina Harry Scherthan 《Experimental cell research》2009,315(15):2593-695
Escape from mitotic catastrophe and generation of endopolyploid tumour cells (ETCs) represents a potential survival strategy of tumour cells in response to genotoxic treatments. ETCs that resume the mitotic cell cycle have reduced ploidy and are often resistant to these treatments. In search for a mechanism for genome reduction, we previously observed that ETCs express meiotic proteins among which REC8 (a meiotic cohesin component) is of particular interest, since it favours reductional cell division in meiosis. In the present investigation, we induced endopolyploidy in p53-dysfunctional human tumour cell lines (Namalwa, WI-L2-NS, HeLa) by gamma irradiation, and analysed the sub-cellular localisation of REC8 in the resulting ETCs. We observed by RT-PCR and Western blot that REC8 is constitutively expressed in these tumour cells, along with SGOL1 and SGOL2, and that REC8 becomes modified after irradiation. REC8 localised to paired sister centromeres in ETCs, the former co-segregating to opposite poles. Furthermore, REC8 localised to the centrosome of interphase ETCs and to the astral poles in anaphase cells where it colocalised with the microtubule-associated protein NuMA. Altogether, our observations indicate that radiation-induced ETCs express features of meiotic cell divisions and that these may facilitate chromosome segregation and genome reduction. 相似文献
12.
The 2 micron plasmid purloins the yeast cohesin complex: a mechanism for coupling plasmid partitioning and chromosome segregation?
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Mehta S Yang XM Chan CS Dobson MJ Jayaram M Velmurugan S 《The Journal of cell biology》2002,158(4):625-637
The yeast 2 micron plasmid achieves high fidelity segregation by coupling its partitioning pathway to that of the chromosomes. Mutations affecting distinct steps of chromosome segregation cause the plasmid to missegregate in tandem with the chromosomes. In the absence of the plasmid stability system, consisting of the Rep1 and Rep2 proteins and the STB DNA, plasmid and chromosome segregations are uncoupled. The Rep proteins, acting in concert, recruit the yeast cohesin complex to the STB locus. The periodicity of cohesin association and dissociation is nearly identical for the plasmid and the chromosomes. The timely disassembly of cohesin is a prerequisite for plasmid segregation. Cohesin-mediated pairing and unpairing likely provides a counting mechanism for evenly partitioning plasmids either in association with or independently of the chromosomes. 相似文献
13.
Sister chromatids are physically connected by cohesin complexes. This sister chromatid cohesion is essential for the biorientation
of chromosomes on the mitotic and meiotic spindle. In many species, cohesion between chromosome arms is partly dissolved in
prophase of mitosis, whereas cohesion is protected at centromeres until the onset of anaphase. In vertebrates, the protein
Sgo1, protein phosphatase 2A, and several other proteins are required for protection of centromeric cohesin in early mitosis.
In fission yeast, the recruitment of heterochromatin protein Swi6/HP1 to centromeres by the histone-methyltransferase Clr4/Suv39h
is required for enrichment of cohesin at centromeres already in interphase. We have tested if the Suv39h–HP1 histone methylation
pathway is also required for enrichment and mitotic protection of cohesin at centromeres in mammalian cells. We show that
cohesin and HP1 proteins partially colocalize at mitotic centromeres but that cohesin localization is not detectably altered
in mouse embryonic fibroblasts that lack Suv39h genes and in which HP1 proteins can, therefore, not be properly enriched in
pericentric heterochromatin. Our data indicate that the Suv39h–HP1 pathway is not essential for enrichment and mitotic protection
of cohesin at centromeres in mammalian cells. 相似文献
14.
Oka Y Suzuki K Yamauchi M Mitsutake N Yamashita S 《Biochemical and biophysical research communications》2011,(4):762-767
The cohesin loading factor NIPBL is required for cohesin to associate with chromosomes and plays a role in DNA double-strand break (DSB) repair. Although the NIPBL homolog Scc2 is recruited to an enzymatically generated DSB and promotes cohesin-dependent DSB repair in yeast, the mechanism of the recruitment remains poorly understood. Here we show that the human NIPBL is recruited to the sites of DNA damage generated by micro-irradiation as well as to the sites of DSBs induced by homing endonuclease, I-PpoI. The recruitment of NIPBL was impaired by RNAi-mediated knockdown of MDC1 or RNF168, both of which also accumulate at DSBs. We also show that the recruitment of NIPBL to the sites of DNA damage is mediated by its C-terminal region containing HEAT repeats and Heterochromatin protein 1 (HP1) interacting motif. Furthermore, NIPBL accumulation at damaged sites was also compromised by HP1γ depletion. Taken together, our study reveals that human NIPBL is a novel protein recruited to DSB sites, and the recruitment is controlled by MDC1, RNF168 and HP1γ. 相似文献