NIPBL

NIPBL
Identifikatori
Aliasi	NIPBL
Vanjski ID-jevi	OMIM: 608667 MGI: 1913976 HomoloGene: 15850 GeneCards: NIPBL
Lokacija gena (čovjek)
Hrom.	Hromosom 5 (čovjek)
Kraj	37,066,413 bp
Lokacija gena (miš)
Hrom.	Hromosom 15 (miš)
Kraj	8,473,947 bp
Ontologija gena
Molekularna funkcija	• mediator complex binding; • chromo shadow domain binding; • protein N-terminus binding; • histone deacetylase binding; • chromatin binding; • protein C-terminus binding; • GO:0001948, GO:0016582 vezivanje za proteine;
Ćelijska komponenta	• SMC loading complex; • nukleoplazma; • Hromatin; • Egzosom; • jedro; • integrator complex; • nuclear chromosome; • hromosom; • Scc2-Scc4 cohesin loading complex;
Biološki proces	• positive regulation of histone deacetylation; • forelimb morphogenesis; • eye morphogenesis; • regulation of embryonic development; • kognitivna funkcija; • uterus morphogenesis; • cellular response to X-ray; • regulation of developmental growth; • heart morphogenesis; • outflow tract morphogenesis; • positive regulation of ossification; • GO:1901227 negative regulation of transcription by RNA polymerase II; • sluh; • 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; • Regulacija ekspresije gena; • embryonic cranial skeleton morphogenesis; • embryonic viscerocranium morphogenesis; • ćelijski ciklus; • metanephros development; • GO:0045996 negative regulation of transcription, DNA-templated; • fat cell differentiation; • maintenance of mitotic sister chromatid cohesion; • embryonic forelimb morphogenesis; • face morphogenesis; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II; • positive regulation of neuron migration; • transcription, DNA-templated; • GO:0009373 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; • Razmjena sestrinskih hromatida;
	Izvori:Amigo / QuickGO
Ortolozi
	25836
	71175
	ENSG00000164190
	ENSMUSG00000022141
	Q6KC79
	Q6KCD5
	NM_015384; NM_133433
	NM_027707; NM_201232
	NP_056199; NP_597677
	NP_081983; NP_957684
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Bradavicoliki protein-B (NIPBL), znan i kao SCC2 ili delangin jest protein koji je kod ljudi kodiran genom NIPBL sa hromosoma 5.^[5] NIPBL je potreban za povezivanje kohezina s DNK i glavna je podjedinica kompleksa za punjenje kohezina.^[6] Heterozigotne mutacije u NIPBL čine oko 60% slučajeva sindroma Cornelije de Lange.^[7]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 2.804 aminokiseline, а molekulska težina 316.051 Da.^[8].

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MNGDMPHVPI	TTLAGIASLT	DLLNQLPLPS	PLPATTTKSL	LFNARIAEEV
NCLLACRDDN	LVSQLVHSLN	QVSTDHIELK	DNLGSDDPEG	DIPVLLQAVL
ARSPNVFREK	SMQNRYVQSG	MMMSQYKLSQ	NSMHSSPASS	NYQQTTISHS
PSSRFVPPQT	SSGNRFMPQQ	NSPVPSPYAP	QSPAGYMPYS	HPSSYTTHPQ
MQQASVSSPI	VAGGLRNIHD	NKVSGPLSGN	SANHHADNPR	HGSSEDYLHM
VHRLSSDDGD	SSTMRNAASF	PLRSPQPVCS	PAGSEGTPKG	SRPPLILQSQ
SLPCSSPRDV	PPDILLDSPE	RKQKKQKKMK	LGKDEKEQSE	KAAMYDIISS
PSKDSTKLTL	RLSRVRSSDM	DQQEDMISGV	ENSNVSENDI	PFNVQYPGQT
SKTPITPQDI	NRPLNAAQCL	SQQEQTAFLP	ANQVPVLQQN	TSVAAKQPQT
SVVQNQQQIS	QQGPIYDEVE	LDALAEIERI	ERESAIERER	FSKEVQDKDK
PLKKRKQDSY	PQEAGGATGG	NRPASQETGS	TGNGSRPALM	VSIDLHQAGR
VDSQASITQD	SDSIKKPEEI	KQCNDAPVSV	LQEDIVGSLK	STPENHPETP
KKKSDPELSK	SEMKQSESRL	AESKPNENRL	VETKSSENKL	ETKVETQTEE
LKQNESRTTE	CKQNESTIVE	PKQNENRLSD	TKPNDNKQNN	GRSETTKSRP
ETPKQKGESR	PETPKQKSDG	HPETPKQKGD	GRPETPKQKG	ESRPETPKQK
NEGRPETPKH	RHDNRRDSGK	PSTEKKPEVS	KHKQDTKSDS	PRLKSERAEA
LKQRPDGRSV	SESLRRDHDN	KQKSDDRGES	ERHRGDQSRV	RRPETLRSSS
RNEHGIKSDS	SKTDKLERKH	RHESGDSRER	PSSGEQKSRP	DSPRVKQGDS
NKSRSDKLGF	KSPTSKDDKR	TEGNKSKVDT	NKAHPDNKAE	FPSYLLGGRS
GALKNFVIPK	IKRDKDGNVT	QETKKMEMKG	EPKDKVEKIG	LVEDLNKGAK
PVVVLQKLSL	DDVQKLIKDR	EDKSRSSLKP	IKNKPSKSNK	GSIDQSVLKE
LPPELLAEIE	STMPLCERVK	MNKRKRSTVN	EKPKYAEISS	DEDNDSDEAF
ESSRKRHKKD	DDKAWEYEER	DRRSSGDHRR	SGHSHEGRRS	SGGGRYRNRS
PSDSDMEDYS	PPPSLSEVAR	KMKKKEKQKK	RKAYEPKLTP	EEMMDSSTFK
RFTASIENIL	DNLEDMDFTA	FGDDDEIPQE	LLLGKHQLNE	LGSESAKIKA
MGIMDKLSTD	KTVKVLNILE	KNIQDGSKLS	TLLNHNNDTE	EEERLWRDLI
MERVTKSADA	CLTTINIMTS	PNMPKAVYIE	DVIERVIQYT	KFHLQNTLYP
QYDPVYRLDP	HGGGLLSSKA	KRAKCSTHKQ	RVIVMLYNKV	CDIVSSLSEL
LEIQLLTDTT	ILQVSSMGIT	PFFVENVSEL	QLCAIKLVTA	VFSRYEKHRQ
LILEEIFTSL	ARLPTSKRSL	RNFRLNSSDM	DGEPMYIQMV	TALVLQLIQC
VVHLPSSEKD	SNAEEDSNKK	IDQDVVITNS	YETAMRTAQN	FLSIFLKKCG
SKQGEEDYRP	LFENFVQDLL	STVNKPEWPA	AELLLSLLGR	LLVHQFSNKS
TEMALRVASL	DYLGTVAARL	RKDAVTSKMD	QGSIERILKQ	VSGGEDEIQQ
LQKALLDYLD	ENTETDPSLV	FSRKFYIAQW	FRDTTLETEK	AMKSQKDEES
SEGTHHAKEI	ETTGQIMHRA	ENRKKFLRSI	IKTTPSQFST	LKMNSDTVDY
DDACLIVRYL	ASMRPFAQSF	DIYLTQILRV	LGENAIAVRT	KAMKCLSEVV
AVDPSILARL	DMQRGVHGRL	MDNSTSVREA	AVELLGRFVL	CRPQLAEQYY
DMLIERILDT	GISVRKRVIK	ILRDICIEQP	TFPKITEMCV	KMIRRVNDEE
GIKKLVNETF	QKLWFTPTPH	NDKEAMTRKI	LNITDVVAAC	RDTGYDWFEQ
LLQNLLKSEE	DSSYKPVKKA	CTQLVDNLVE	HILKYEESLA	DSDNKGVNSG
RLVACITTLF	LFSKIRPQLM	VKHAMTMQPY	LTTKCSTQND	FMVICNVAKI
LELVVPLMEH	PSETFLATIE	EDLMKLIIKY	GMTVVQHCVS	CLGAVVNKVT
QNFKFVWACF	NRYYGAISKL	KSQHQEDPNN	TSLLTNKPAL	LRSLFTVGAL
CRHFDFDLED	FKGNSKVNIK	DKVLELLMYF	TKHSDEEVQT	KAIIGLGFAF
IQHPSLMFEQ	EVKNLYNNIL	SDKNSSVNLK	IQVLKNLQTY	LQEEDTRMQQ
ADRDWKKVAK	QEDLKEMGDV	SSGMSSSIMQ	LYLKQVLEAF	FHTQSSVRHF
ALNVIALTLN	QGLIHPVQCV	PYLIAMGTDP	EPAMRNKADQ	QLVEIDKKYA
GFIHMKAVAG	MKMSYQVQQA	INTCLKDPVR	GFRQDESSSA	LCSHLYSMIR
GNRQHRRAFL	ISLLNLFDDT	AKTDVTMLLY	IADNLACFPY	QTQEEPLFIM
HHIDITLSVS	GSNLLQSFKE	SMVKDKRKER	KSSPSKENES	SDSEEEVSRP
RKSRKRVDSD	SDSDSEDDIN	SVMKCLPENS	APLIEFANVS	QGILLLLMLK
QHLKNLCGFS	DSKIQKYSPS	ESAKVYDKAI	NRKTGVHFHP	KQTLDFLRSD
MANSKITEEV	KRSIVKQYLD	FKLLMEHLDP	DEEEEEGEVS	ASTNARNKAI
TSLLGGGSPK	NNTAAETEDD	ESDGEDRGGG	TSGSLRRSKR	NSDSTELAAQ
MNESVDVMDV	IAICCPKYKD	RPQIARVVQK	TSSGFSVQWM	AGSYSGSWTE
AKRRDGRKLV	PWVDTIKESD	IIYKKIALTS	ANKLTNKVVQ	TLRSLYAAKD
GTSS

Struktura i interakcije

NIPBL je veliki kukasti protein koji sadrži HEAT-ponavljanje.^[9] Formira kompleks sa MAU2 (SCC4 u pupajućem kvascu), poznat kao kompleks kohezinskog utovara.^[10] Kako ovo ime sugerira, NiPBL i MAU2 potrebni su za početno udruženje kohezina sa DNK.

Smatra se da kohezin posreduje interakcije poboljšavač-promotor i generira topološki udružujuće domene (TADS) kao i posredovanje kohezije i reguliranje arhitekture DNK. Kompleks kohezina potreban je za popravak DNK homolognom rekombinacijom. S obzirom da je NIPBL potreban za udruživanje kohezina s DNK, smatra se da je i NiPBL potreban za sve ove procese. Dosljedno, inaktivacija NiPBL-a rezultira u topološkom udruživanju gubitaka i kohezije.^[11]

NIPBL se dinamički veže na hromatin, glavnim putem udruživanja sa kohezinom.^[12] Kretanje NiPBL-a unutar hromatina u skladu je sa mehanizmom koji uključuje skakanje između hromosomkog koheziranja prstenova. Pokazana je i kohezina nezavisna regulacijia ekspresija odgovornog gena.^[13]^[14]

Klinički značaj

Mutacije u ovom genu rezultiraju sindromom Cornelije de Lange (CDLS), poremećaj koji karakterizira dismorfne karakteristike lica, kašnjenje rasta, smanjenje dužine udova i mentalna invalidnost^[5] kao što su ove mutacije. Obično su heterozigotni CD-ovi pogođeni smanjenjem NiPBL-a nije potpuni gubitak. Eksperimenti na ćelijama pacijenata i miševa pokazuju da je smanjenje za manje od polovine.^[15] Nije poznato zašto se javlja smanjenje ekspresije NIPBL u CDL-ovima.

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000164190 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000022141 - Ensembl, maj 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 (juli 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.
^ "UniProt, Q6KC79" (jezik: engleski). Pristupljeno 17. 10. 2021.
^ Kikuchi S, Borek DM, Otwinowski Z, Tomchick DR, Yu H (novembar 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. doi:10.1073/pnas.1611333113. PMC 5098657. PMID 27791135.
^ Nasmyth K (oktobar 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.
^ Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K (februar 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 (februar 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, Urbán N, Dekkers DH, Demmers JA, Guillemot F (januar 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 (septembar 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.

Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000164190 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000022141 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: Nipped-B homolog (Drosophila)".

[Ciosk_2000-6] 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.

[7] Rohatgi S, Clark D, Kline AD, Jackson LG, Pie J, Siu V, Ramos FJ, Krantz ID, Deardorff MA (juli 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.

[UniProt-8] "UniProt, Q6KC79" (jezik: engleski). Pristupljeno 17. 10. 2021.

[9] Kikuchi S, Borek DM, Otwinowski Z, Tomchick DR, Yu H (novembar 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. doi:10.1073/pnas.1611333113. PMC 5098657. PMID 27791135.

[10] Nasmyth K (oktobar 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.

[11] Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K (februar 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.

[pmid28914604-12] 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.

[13] Zuin J, Franke V, van Ijcken WF, van der Sloot A, Krantz ID, van der Reijden MI, Nakato R, Lenhard B, Wendt KS (februar 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.

[14] van den Berg DL, Azzarelli R, Oishi K, Martynoga B, Urbán N, Dekkers DH, Demmers JA, Guillemot F (januar 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.

[15] 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 (septembar 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.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]