Nipped-B-like protein (NIPBL), also known as SCC2 or delangin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''NIPBL''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. NIPBL is required for the association of

cohesin Cohesin is a protein complex that mediates Establishment of sister chromatid cohesion, sister chromatid cohesion, homologous recombination, and Topologically associating domain, DNA looping. Cohesin is formed of SMC3, SMC1A, SMC1, RAD21, SCC1 an ...

with DNA and is the major subunit of the cohesin loading complex. Heterozygous mutations in ''NIPBL'' account for an estimated 60% of case of

Cornelia de Lange Syndrome 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, ...

Structure and Interactions

NIPBL is a large hook-shaped protein containing

HEAT repeat A HEAT repeat is a Protein tandem repeats, protein tandem repeat structural motif composed of two alpha helices linked by a short loop. HEAT repeats can form alpha solenoids, a type of solenoid protein domain found in a number of cytoplasmic prot ...

s. NIPBL forms a complex with MAU2 (Scc4 in budding yeast) known as the cohesin loading complex. 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 Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...

. 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 and cohesion. NIPBL binds dynamically to

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

principally through an association with

. NIPBL’s movement within chromatin is consistent with a mechanism involving hopping between

chromosomal A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most importa ...

cohesin rings. A cohesin-independent function in the regulation of gene expression has also been demonstrated for NIPBL.

Clinical significance

Mutations in this gene result in

Cornelia de Lange syndrome 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, ...

(CdLS), a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and mental retardation. As these mutations are usually

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

, 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. It is not known why a reduction in Nipbl expression results in CdLS.

References

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