Nipped-B-like protein (NIPBL), also known as SCC2 or delangin is a protein that in humans is encoded by the NIPBLgene.[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]
Structure of SCC4 (green) in complex with SCC2 N-terminal domain (blue) from budding yeast (Hinshaw et al., 2015)
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]
Clinical significanceedit
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.
Referencesedit
^ abcGRCh38: Ensembl release 89: ENSG00000164190 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000022141 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K (2000). "Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins". Molecular Cell. 5 (2): 243–54. doi:10.1016/S1097-2765(00)80420-7. PMID 10882066.
^Rohatgi S, Clark D, Kline AD, Jackson LG, Pie J, Siu V, Ramos FJ, Krantz ID, Deardorff MA (July 2010). "Facial diagnosis of mild and variant CdLS: Insights from a dysmorphologist survey". American Journal of Medical Genetics. Part A. 152A (7): 1641–53. doi:10.1002/ajmg.a.33441. PMC4133091. PMID 20583156.
^Kikuchi S, Borek DM, Otwinowski Z, Tomchick DR, Yu H (November 2016). "Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy". Proceedings of the National Academy of Sciences of the United States of America. 113 (44): 12444–12449. Bibcode:2016PNAS..11312444K. doi:10.1073/pnas.1611333113. PMC5098657. PMID 27791135.
^Nasmyth K (October 2011). "Cohesin: a catenase with separate entry and exit gates?". Nature Cell Biology. 13 (10): 1170–7. doi:10.1038/ncb2349. PMID 21968990. S2CID 25382204.
^Schwarzer W, Abdennur N, Goloborodko A, Pekowska A, Fudenberg G, Loe-Mie Y, Fonseca NA, Huber W, Haering C, Mirny L, Spitz F (15 December 2016). "Two independent modes of chromosome organization are revealed by cohesin removal". p. 094185. bioRxiv10.1101/094185.
^Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K (February 2000). "Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins". Molecular Cell. 5 (2): 243–54. doi:10.1016/s1097-2765(00)80420-7. PMID 10882066.
^Rhodes J, Mazza D, Nasmyth K, Uphoff S (2017). "Scc2/Nipbl hops between chromosomal cohesin rings after loading". eLife. 6. doi:10.7554/eLife.30000. PMC5621834. PMID 28914604.
^Zuin J, Franke V, van Ijcken WF, van der Sloot A, Krantz ID, van der Reijden MI, Nakato R, Lenhard B, Wendt KS (February 2014). "A cohesin-independent role for NIPBL at promoters provides insights in CdLS". PLOS Genetics. 10 (2): e1004153. doi:10.1371/journal.pgen.1004153. PMC3923681. PMID 24550742.
^van den Berg DL, Azzarelli R, Oishi K, Martynoga B, Urbán N, Dekkers DH, Demmers JA, Guillemot F (January 2017). "Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration". Neuron. 93 (2): 348–361. doi:10.1016/j.neuron.2016.11.047. PMC5263256. PMID 28041881.
^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 (September 2009). "Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome". PLOS Genetics. 5 (9): e1000650. doi:10.1371/journal.pgen.1000650. PMC2730539. PMID 19763162.
nipbl, nipped, like, protein, also, known, scc2, delangin, protein, that, humans, encoded, gene, required, association, cohesin, with, major, subunit, cohesin, loading, complex, heterozygous, mutations, account, estimated, case, cornelia, lange, syndrome, iden. 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 NIPBLIdentifiersAliasesNIPBL CDLS CDLS1 IDN3 IDN3 B Scc2 cohesin loading factor NIPBL cohesin loading factorExternal IDsOMIM 608667 MGI 1913976 HomoloGene 15850 GeneCards NIPBLGene location Human Chr Chromosome 5 human 1 Band5p13 2Start36 876 769 bp 1 End37 066 413 bp 1 Gene location Mouse Chr Chromosome 15 mouse 2 Band15 15 A1Start8 320 101 bp 2 End8 473 947 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inAchilles tendonganglionic eminencepancreatic ductal cellinternal globus pallidussural nervevisceral pleurathymusmonocytebone marrow cellsendothelial cellTop expressed ininternal carotid arterymaxillary prominenceexternal carotid arteryPaneth celllacrimal glandseminiferous tubulehair folliclepineal glandconjunctival fornixbody of femurMore reference expression dataBioGPSn aGene ontologyMolecular functionmediator complex binding chromo shadow domain binding protein N terminus binding histone deacetylase binding chromatin binding protein C terminus binding protein bindingCellular componentSMC loading complex nucleoplasm chromatin extracellular exosome nucleus integrator complex nuclear chromosome chromosome Scc2 Scc4 cohesin loading complexBiological processpositive regulation of histone deacetylation forelimb morphogenesis eye morphogenesis regulation of embryonic development cognition uterus morphogenesis cellular response to X ray regulation of developmental growth heart morphogenesis outflow tract morphogenesis positive regulation of ossification negative regulation of transcription by RNA polymerase II sensory perception of sound cellular response to DNA damage stimulus stem cell population maintenance ear morphogenesis heart development brain development developmental growth external genitalia morphogenesis regulation of hair cycle positive regulation of multicellular organism growth embryonic digestive tract morphogenesis gall bladder development regulation of gene expression embryonic cranial skeleton morphogenesis embryonic viscerocranium morphogenesis cell cycle metanephros development negative regulation of transcription DNA templated fat cell differentiation maintenance of mitotic sister chromatid cohesion embryonic forelimb morphogenesis face morphogenesis positive regulation of transcription by RNA polymerase II regulation of transcription by RNA polymerase II positive regulation of neuron migration transcription DNA templated regulation of transcription DNA templated multicellular organism development mitotic sister chromatid cohesion double strand break repair mitotic chromosome condensation establishment of mitotic sister chromatid cohesion rDNA condensation establishment of protein localization to chromatin cohesin loading positive regulation of mitotic cohesin loading replication born double strand break repair via sister chromatid exchangeSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez2583671175EnsemblENSG00000164190ENSMUSG00000022141UniProtQ6KC79Q6KCD5RefSeq mRNA NM 015384NM 133433NM 027707NM 201232RefSeq protein NP 056199NP 597677NP 081983NP 957684Location UCSC Chr 5 36 88 37 07 MbChr 15 8 32 8 47 MbPubMed search 3 4 WikidataView Edit HumanView Edit MouseStructure and Interactions edit nbsp Structure of SCC4 green in complex with SCC2 N terminal domain blue from budding yeast Hinshaw et al 2015 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 Clinical significance editMutations 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 References edit a b c GRCh38 Ensembl release 89 ENSG00000164190 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000022141 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine a b Entrez Gene Nipped B homolog Drosophila Ciosk R Shirayama M Shevchenko A Tanaka T Toth A Shevchenko A Nasmyth K 2000 Cohesin s binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins Molecular Cell 5 2 243 54 doi 10 1016 S1097 2765 00 80420 7 PMID 10882066 Rohatgi S Clark D Kline AD Jackson LG Pie J Siu V Ramos FJ Krantz ID Deardorff MA July 2010 Facial diagnosis of mild and variant CdLS Insights from a dysmorphologist survey American Journal of Medical Genetics Part A 152A 7 1641 53 doi 10 1002 ajmg a 33441 PMC 4133091 PMID 20583156 Kikuchi S Borek DM Otwinowski Z Tomchick DR Yu H November 2016 Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy Proceedings of the National Academy of Sciences of the United States of America 113 44 12444 12449 Bibcode 2016PNAS 11312444K doi 10 1073 pnas 1611333113 PMC 5098657 PMID 27791135 Nasmyth K October 2011 Cohesin a catenase with separate entry and exit gates Nature Cell Biology 13 10 1170 7 doi 10 1038 ncb2349 PMID 21968990 S2CID 25382204 Schwarzer W Abdennur N Goloborodko A Pekowska A Fudenberg G Loe Mie Y Fonseca NA Huber W Haering C Mirny L Spitz F 15 December 2016 Two independent modes of chromosome organization are revealed by cohesin removal p 094185 bioRxiv 10 1101 094185 Ciosk R Shirayama M Shevchenko A Tanaka T Toth A Shevchenko A Nasmyth K February 2000 Cohesin s binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins Molecular Cell 5 2 243 54 doi 10 1016 s1097 2765 00 80420 7 PMID 10882066 Rhodes J Mazza D Nasmyth K Uphoff S 2017 Scc2 Nipbl hops between chromosomal cohesin rings after loading eLife 6 doi 10 7554 eLife 30000 PMC 5621834 PMID 28914604 Zuin J Franke V van Ijcken WF van der Sloot A Krantz ID van der Reijden MI Nakato R Lenhard B Wendt KS February 2014 A cohesin independent role for NIPBL at promoters provides insights in CdLS PLOS Genetics 10 2 e1004153 doi 10 1371 journal pgen 1004153 PMC 3923681 PMID 24550742 van den Berg DL Azzarelli R Oishi K Martynoga B Urban N Dekkers DH Demmers JA Guillemot F January 2017 Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration Neuron 93 2 348 361 doi 10 1016 j neuron 2016 11 047 PMC 5263256 PMID 28041881 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 September 2009 Multiple organ system defects and transcriptional dysregulation in the Nipbl mouse a model of Cornelia de Lange Syndrome PLOS Genetics 5 9 e1000650 doi 10 1371 journal pgen 1000650 PMC 2730539 PMID 19763162 This article incorporates text from the United States National Library of Medicine which is in the public domain nbsp This article on a gene on human chromosome 5 is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title NIPBL amp oldid 1188036691, wikipedia, wiki, book, books, library,
