Nipped-B-like protein (NIPBL), also known as SCC2 or delangin is a protein that in humans is encoded by the NIPBL gene. [5] NIPBL is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex. [6] Heterozygous mutations in NIPBL account for an estimated 60% of case of Cornelia de Lange Syndrome. [7]
NIPBL is a large hook-shaped protein containing HEAT repeats. [8] NIPBL forms a complex with MAU2 (Scc4 in budding yeast) known as the cohesin loading complex. [9] As this name suggests NIPBL and MAU2 are required for the initial association of cohesin with DNA.
Cohesin is thought to mediate enhancer-promoter interactions and generate Topologically associating domains (TADs). As well as mediating cohesion and regulating DNA architecture the cohesin complex is required for DNA repair by homologous recombination. Given that NIPBL is required for cohesin's association with DNA it is thought that NIPBL is also required for all of these processes. Consistently, inactivation of Nipbl results in the loss topologically associating domains [10] and cohesion. [11]
NIPBL binds dynamically to chromatin principally through an association with cohesin. [12] NIPBL’s movement within chromatin is consistent with a mechanism involving hopping between chromosomal cohesin rings. A cohesin-independent function in the regulation of gene expression has also been demonstrated for NIPBL. [13] [14]
Mutations in this gene result in Cornelia de Lange syndrome (CdLS), a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and mental retardation. [5] As these mutations are usually heterozygous, CdLS is caused by a reduction in the abundance of Nipbl, not a complete loss. Experiments on cells from patients and mice indicate that the reduction is by less than half. [15] It is not known why a reduction in Nipbl expression results in CdLS.
Kim Ashley Nasmyth is an English geneticist, the Whitley Professor of Biochemistry at the University of Oxford, a Fellow of Trinity College, Oxford, former scientific director of the Research Institute of Molecular Pathology (IMP), and former head of the Department of Biochemistry, University of Oxford. He is best known for his work on the segregation of chromosomes during cell division.
Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene.
SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. SMC stands for Structural Maintenance of Chromosomes.
Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.
Cornelia de Lange syndrome (CdLS) is a genetic disorder. People with Cornelia de Lange syndrome experience a range of physical, cognitive, and medical challenges ranging from mild to severe. Cornelia de Lange syndrome has a widely varied phenotype, meaning people with the syndrome have varied features and challenges. The typical features of CdLS include thick or long eyebrows, a small nose, small stature, developmental delay, long or smooth philtrum, thin upper lip and downturned mouth.
Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the SMC1A gene. SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells, cohesin is formed of SMC1A, SMC3, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.
Protection of telomeres protein 1 is a protein that in humans is encoded by the POT1 gene.
Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the RAD21 gene. RAD21, an essential gene, encodes a DNA double-strand break (DSB) repair protein that is evolutionarily conserved in all eukaryotes from budding yeast to humans. RAD21 protein is a structural component of the highly conserved cohesin complex consisting of RAD21, SMC1A, SMC3, and SCC3 [ STAG1 (SA1) and STAG2 (SA2) in multicellular organisms] proteins, involved in sister chromatid cohesion.
Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. In humans, SMC3 is present in all cohesin complexes whereas there are multiple paralogs for the other subunits.
Cohesin subunit SA-2 (SA2) is a protein that in humans is encoded by the STAG2 gene. SA2 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.
Kinesin family member 5A is a protein that in humans is encoded by the KIF5A gene. It is part of the kinesin family of motor proteins.
Wings apart-like protein homolog (WAPL) is a protein that in humans is encoded by the WAPAL gene. WAPL is a key regulator of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. Cohesin has a ring-like arrangement and it is thought that it associates with the chromosome by entrapping it whether as a loop of DNA, a single strand or a pair of sister chromosomes. WAPL forms a complex with PDS5A or PDS5B and releases cohesin from DNA by opening the interface between SMC3 and RAD21.
Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the REC8 gene.
Structural maintenance of chromosomes protein 2 (SMC-2), also known as chromosome-associated protein E (CAP-E), is a protein that in humans is encoded by the SMC2 gene. SMC2 is part of the SMC protein family and is a core subunit of condensin I and II, large protein complexes involved in chromosome condensation, overall organization. Several studies have demonstrated the necessity of SMC2 for cell division and proliferation.
Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles.
Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC proteins engage in chromosome organization and can be broken into 3 groups based on function which are cohesins, condensins, and DNA repair. SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1ß protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.
Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 (Sac3) is an enzyme that in humans is encoded by the FIG4 gene. Fig4 is an abbreviation for Factor-Induced Gene.
Stromal antigen 3 is a protein that in humans is encoded by the STAG3 gene. STAG3 protein is a component of a cohesin complex that regulates the separation of sister chromatids specifically during meiosis. STAG3 appears to be paramount in sister-chromatid cohesion throughout the meiotic process in human oocytes and spermatocytes.
Frank Uhlmann FRS is a group leader at the Francis Crick Institute in London.
Nuclear organization refers to the spatial distribution of chromatin within a cell nucleus. There are many different levels and scales of nuclear organisation. Chromatin is a higher order structure of DNA.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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