Cohesin: Its Roles and Mechanisms

Nasmyth, Kim; Haering, Christian H.

doi:10.1146/annurev-genet-102108-134233

Cited by 878 publications

(967 citation statements)

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“…17 It was subsequently demonstrated that NIPBL/Scc2 regulates cohesin, 18,19 a complex composed of four highly conserved subunits: SMC1, SMC3, SCC1/RAD21 and SCC3/STAG. 20 Although initially identified for its role in sister chromatid cohesion, recent evidence has demonstrated additional functions.…”

Section: Cdlsmentioning

confidence: 99%

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

et al. 2011

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Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIPBL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIPBL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.

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Section: Cdlsmentioning

confidence: 99%

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

et al. 2011

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“…To determine the role of cohesin in interphase chromatin, we deleted NIPBL / SCC2 , the factor which is necessary for cohesin loading on chromatin 22 . Since the turnover of chromosome-bound cohesin is ~20 minutes 23,24 , constant loading is required for its presence on DNA.…”

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confidence: 99%

Two independent modes of chromatin organization revealed by cohesin removal

Schwarzer

Abdennur

Goloborodko

et al. 2017

Nature

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Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-large active and inactive compartments, and partitioning into sub-megabase domains (TADs). Yet, it remains unclear how these layers of organization form, interact with one another and impact genome functions. Here, we show that deletion of the cohesin-loading factor Nipbl, in mouse liver, leads to a dramatic reorganization of chromosomal folding. TADs and associated peaks vanish globally, even in the absence of transcriptional changes. In contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the 3D organization of the genome results from the interplay of two independent mechanisms: 1) cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; 2) cohesin-dependent formation of TADs, possibly by loop extrusion, which contributes to guide distant enhancers to their target genes.

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“…Cohesin is essential for DNA repair and chromosome segregation [1,2]. Heterozygous cohesin mutations are the cause of multi-systems developmental disorder such as Cornelia de Lange syndrome [3][4][5], and cohesin mutations have also been reported in cancer [6][7][8].…”

Section: Overviewmentioning

confidence: 99%

“…Aptly named 'SMC' proteins for 'structural maintenance of chromosomes' cohesin, condensin and Smc5/6 complexes maintain the integrity of genetic information by enabling postreplicative DNA repair, shaping chromosomes in preparation for cell division, and holding sister chromatids together to ensure that daughter cells receive a full complement of chromosomes.Cohesin is essential for DNA repair and chromosome segregation [1,2]. Heterozygous cohesin mutations are the cause of multi-systems developmental disorder such as Cornelia de Lange syndrome [3][4][5], and cohesin mutations have also been reported in cancer [6][7][8].…”

mentioning

confidence: 99%

“…In mammalian cells cohesin is loaded onto chromosomes at the end of mitosis by a separate complex consisting of Nipbl (also known as Nipped-B or Scc2) and Mau-2 (also known as Scc4) [22][23][24][25][26]. Although there are dissenting views, cohesin is thought to associate with chromosomes by 'topological embrace' [1] or, more prosaically, by trapping chromosomes inside its ring-like structure. The stability of cohesin binding is regulated by additional proteins in a cell cycle-dependent manner.…”

mentioning

confidence: 99%

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