NIPBL

File:Structure of SCC4 (green) in complex with SCC2 N-terminal domain (blue) from budding yeast (Hinshaw et al., 2015).png

NIPBL is a large hook-shaped protein containing HEAT repeats.{{cite journal | vauthors = Kikuchi S, Borek DM, Otwinowski Z, Tomchick DR, Yu H | title = Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 44 | pages = 12444–12449 | date = November 2016 | pmid = 27791135 | doi = 10.1073/pnas.1611333113 | pmc=5098657| bibcode = 2016PNAS..11312444K | doi-access = free }} NIPBL forms a complex with MAU2 (Scc4 in budding yeast) known as the cohesin loading complex.{{cite journal | vauthors = Nasmyth K | title = Cohesin: a catenase with separate entry and exit gates? | journal = Nature Cell Biology | volume = 13 | issue = 10 | pages = 1170–7 | date = October 2011 | pmid = 21968990 | doi = 10.1038/ncb2349 | s2cid = 25382204 }} 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{{cite bioRxiv | last1 = Schwarzer | first1 = Wibke | last2 = Abdennur | first2 = Nezar | last3 = Goloborodko | first3 = Anton | last4 = Pekowska | first4 = Aleksandra | last5 = Fudenberg | first5 = Geoffrey | last6 = Loe-Mie | first6 = Yann | last7 = Fonseca | first7 = Nuno A. | last8 = Huber | first8 = Wolfgang | last9 = Haering | first9 = Christian | last10 = Mirny | first10 = Leonid | last11 = Spitz | first11 = François | name-list-style = vanc |title=Two independent modes of chromosome organization are revealed by cohesin removal|date=15 December 2016|pages=094185|biorxiv=10.1101/094185}} and cohesion.{{cite journal | vauthors = Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K | title = Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins | journal = Molecular Cell | volume = 5 | issue = 2 | pages = 243–54 | date = February 2000 | pmid = 10882066 | doi=10.1016/s1097-2765(00)80420-7| doi-access = free }}

NIPBL binds dynamically to chromatin principally through an association with cohesin.{{cite journal |vauthors=Rhodes J, Mazza D, Nasmyth K, Uphoff S |title=Scc2/Nipbl hops between chromosomal cohesin rings after loading |journal=eLife |volume=6 |year=2017 |pmid=28914604 |pmc=5621834 |doi=10.7554/eLife.30000 |doi-access=free }} 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.{{cite journal | vauthors = Zuin J, Franke V, van Ijcken WF, van der Sloot A, Krantz ID, van der Reijden MI, Nakato R, Lenhard B, Wendt KS | title = A cohesin-independent role for NIPBL at promoters provides insights in CdLS | journal = PLOS Genetics | volume = 10 | issue = 2 | pages = e1004153 | date = February 2014 | pmid = 24550742 | doi = 10.1371/journal.pgen.1004153 | pmc=3923681 | doi-access = free }}{{cite journal | vauthors = van den Berg DL, Azzarelli R, Oishi K, Martynoga B, Urbán N, Dekkers DH, Demmers JA, Guillemot F | title = Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration | journal = Neuron | volume = 93 | issue = 2 | pages = 348–361 | date = January 2017 | pmid = 28041881 | doi = 10.1016/j.neuron.2016.11.047 | pmc=5263256}}

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. 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.{{cite journal | vauthors = Kawauchi S, Calof AL, Santos R, Lopez-Burks ME, Young CM, Hoang MP, Chua A, Lao T, Lechner MS, Daniel JA, Nussenzweig A, Kitzes L, Yokomori K, Hallgrimsson B, Lander AD | title = Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome | journal = PLOS Genetics | volume = 5 | issue = 9 | pages = e1000650 | date = September 2009 | pmid = 19763162 | doi = 10.1371/journal.pgen.1000650 | pmc=2730539 | doi-access = free }} It is not known why a reduction in Nipbl expression results in CdLS.

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