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Gause M Webber HA Misulovin Z Haller G Rollins RA Eissenberg JC Bickel SE Dorsett D 《Chromosoma》2008,117(1):51-66
Drosophila Nipped-B is an essential protein that has multiple functions. It facilitates expression of homeobox genes and is also required
for sister chromatid cohesion. Nipped-B is conserved from yeast to man, and its orthologs also play roles in deoxyribonucleic
acid repair and meiosis. Mutation of the human ortholog, Nipped-B-Like (NIPBL), causes Cornelia de Lange syndrome (CdLS),
associated with multiple developmental defects. The Nipped-B protein family is required for the cohesin complex that mediates
sister chromatid cohesion to bind to chromosomes. A key question, therefore, is whether the Nipped-B family regulates gene
expression, meiosis, and development by controlling cohesin. To gain insights into Nipped-B’s functions, we compared the effects
of several Nipped-B mutations on gene expression, sister chromatid cohesion, and meiosis. We also examined association of Nipped-B and cohesin
with somatic and meiotic chromosomes by immunostaining. Missense Nipped-B alleles affecting the same HEAT repeat motifs as CdLS-causing NIPBL mutations have intermediate effects on both gene expression and mitotic chromatid cohesion, linking these two functions and
the role of NIPBL in human development. Nipped-B colocalizes extensively with cohesin on chromosomes in both somatic and meiotic
cells and is present in soluble complexes with cohesin subunits in nuclear extracts. In meiosis, Nipped-B also colocalizes
with the synaptonemal complex and contributes to maintenance of meiotic chromosome cores. These results support the idea that
direct regulation of cohesin function underlies the diverse functions of Nipped-B and its orthologs.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Gause, Webber, and Misulovin provided equal contributions. 相似文献
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NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations
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Gillis LA McCallum J Kaur M DeScipio C Yaeger D Mariani A Kline AD Li HH Devoto M Jackson LG Krantz ID 《American journal of human genetics》2004,75(4):610-623
The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations. 相似文献
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Roles of the sister chromatid cohesion apparatus in gene expression,development, and human syndromes 总被引:3,自引:3,他引:0
Dorsett D 《Chromosoma》2007,116(1):1-13
The sister chromatid cohesion apparatus mediates physical pairing of duplicated chromosomes. This pairing is essential for
appropriate distribution of chromosomes into the daughter cells upon cell division. Recent evidence shows that the cohesion
apparatus, which is a significant structural component of chromosomes during interphase, also affects gene expression and
development. The Cornelia de Lange (CdLS) and Roberts/SC phocomelia (RBS/SC) genetic syndromes in humans are caused by mutations
affecting components of the cohesion apparatus. Studies in Drosophila suggest that effects on gene expression are most likely responsible for developmental alterations in CdLS. Effects on chromatid
cohesion are apparent in RBS/SC syndrome, but data from yeast and Drosophila point to the likelihood that changes in expression of genes located in heterochromatin could contribute to the developmental
deficits. 相似文献
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Metazoan Scc4 homologs link sister chromatid cohesion to cell and axon migration guidance 总被引:2,自引:0,他引:2
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Seitan VC Banks P Laval S Majid NA Dorsett D Rana A Smith J Bateman A Krpic S Hostert A Rollins RA Erdjument-Bromage H Tempst P Benard CY Hekimi S Newbury SF Strachan T 《PLoS biology》2006,4(8):e242
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Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome 总被引:5,自引:0,他引:5
Zhang B Jain S Song H Fu M Heuckeroth RO Erlich JM Jay PY Milbrandt J 《Development (Cambridge, England)》2007,134(17):3191-3201
PDS5B is a sister chromatid cohesion protein that is crucial for faithful segregation of duplicated chromosomes in lower organisms. Mutations in cohesion proteins are associated with the developmental disorder Cornelia de Lange syndrome (CdLS) in humans. To delineate the physiological roles of PDS5B in mammals, we generated mice lacking PDS5B (APRIN). Pds5B-deficient mice died shortly after birth. They exhibited multiple congenital anomalies, including heart defects, cleft palate, fusion of the ribs, short limbs, distal colon aganglionosis, abnormal migration and axonal projections of sympathetic neurons, and germ cell depletion, many of which are similar to abnormalities found in humans with CdLS. Unexpectedly, we found no cohesion defects in Pds5B(-/-) cells and detected high PDS5B expression in post-mitotic neurons in the brain. These results, along with the developmental anomalies of Pds5B(-/-) mice, the presence of a DNA-binding domain in PDS5B in vertebrates and its nucleolar localization, suggest that PDS5B and the cohesin complex have important functions beyond their role in chromosomal dynamics. 相似文献
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Alexander R. Ball Jr. Yen-Yun ChenKyoko Yokomori 《Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms》2014,1839(3):191-202
Cohesins are conserved and essential Structural Maintenance of Chromosomes (SMC) protein-containing complexes that physically interact with chromatin and modulate higher-order chromatin organization. Cohesins mediate sister chromatid cohesion and cellular long-distance chromatin interactions affecting genome maintenance and gene expression. Discoveries of mutations in cohesin's subunits and its regulator proteins in human developmental disorders, so-called “cohesinopathies,” reveal crucial roles for cohesins in development and cellular growth and differentiation. In this review, we discuss the latest findings concerning cohesin's functions in higher-order chromatin architecture organization and gene regulation and new insight gained from studies of cohesinopathies. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development. 相似文献
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刘石娟 《中国生物化学与分子生物学报》2008,24(11):1014-1020
黏着素(cohesin)是一种多亚基蛋白复合体,在进化上相当保守。在真核生物细胞中,黏着素主要功能是将复制产生的姐妹染色单体连接在一起,直到细胞分裂的后期,黏着素亚基Scc1水解最终导致染色单体的分离。但是最近研究表明,黏着素在基因表达、染色质结构变化和发育调节等方面也起着非常重要的作用,并且发现黏着素对基因的调节作用与其对染色体的黏着功能无关。在酵母中,黏着素最初定位于其装载蛋白Scc2的DNA结合位点上,但是在细胞周期的G2期,黏着素聚集于转录汇集区之间进而调控转录终止。在果蝇染色体上,黏着素与装载蛋白Scc2的同源物Nipped-B共定位,其作用是阻抑增强子和启动子的远距离接触。而在哺乳动物中,黏着素与CTCF隔离子蛋白共定位,并以依赖于CTCF的方式调控转录。本文概述了黏着素在不同真核生物染色体上的定位与分布,并对其在基因表达调控中的功能机制及其研究现状进行了重点阐述。 相似文献
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Nipped-B, a Drosophila homologue of chromosomal adherins, participates in activation by remote enhancers in the cut and Ultrabithorax genes. 总被引:6,自引:0,他引:6
How enhancers are able to activate promoters located several kilobases away is unknown. Activation by the wing margin enhancer in the cut gene, located 85 kb from the promoter, requires several genes that participate in the Notch receptor pathway in the wing margin, including scalloped, vestigial, mastermind, Chip, and the Nipped locus. Here we show that Nipped mutations disrupt one or more of four essential complementation groups: l(2)41Ae, l(2)41Af, Nipped-A, and Nipped-B. Heterozygous Nipped mutations modify Notch mutant phenotypes in the wing margin and other tissues, and magnify the effects that mutations in the cis regulatory region of cut have on cut expression. Nipped-A and l(2)41Af mutations further diminish activation by a wing margin enhancer partly impaired by a small deletion. In contrast, Nipped-B mutations do not diminish activation by the impaired enhancer, but increase the inhibitory effect of a gypsy transposon insertion between the enhancer and promoter. Nipped-B mutations also magnify the effect of a gypsy insertion in the Ultrabithorax gene. Gypsy binds the Suppressor of Hairy-wing insulator protein [Su(Hw)] that blocks enhancer-promoter communication. Increased insulation by Su(Hw) in Nipped-B mutants suggests that Nipped-B products structurally facilitate enhancer-promoter communication. Compatible with this idea, Nipped-B protein is homologous to a family of chromosomal adherins with broad roles in sister chromatid cohesion, chromosome condensation, and DNA repair. 相似文献
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The centromere-kinetochore complex is a highly specialized chromatin domain that both mediates and monitors chromosome-spindle interactions responsible for accurate partitioning of sister chromatids to daughter cells. Centromeres are distinguished from adjacent chromatin by specific patterns of histone modification and the presence of a centromere-specific histone H3 variant (e.g. CENP-A). Centromere-proximal regions usually correspond to sites of avid and persistent sister chromatid cohesion mediated by the conserved cohesin complex. In budding yeast, there is a substantial body of evidence indicating centromeres direct formation and/or stabilization of centromere-proximal cohesion. In other organisms, the dependency of cohesion on centromere function is not as clear. Indeed, it appears that pericentromeric heterochromatin recruits cohesion proteins independent of centromere function. Nonetheless, aspects of centromere function are impaired in the absence of sister chromatid cohesion, suggesting the two are interdependent. Here we review the nature of centromeric chromatin, the dynamics and regulation of sister chromatid cohesion, and the relationship between the two. 相似文献