NCAPH

NCAPH
Identifiers
Aliases	NCAPH , BRRN1, CAP-H, non-SMC condensin I complex subunit H, MCPH23, CAPH
External IDs	OMIM: 602332 MGI: 2444777 HomoloGene: 133986 GeneCards: NCAPH
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2q11.2 Start 96,335,766 bp [1] End 96,377,091 bp [1]
Gene location (Mouse) Chr. Chromosome 2 (mouse) [2] Band 2|2 F1 Start 126,945,729 bp [2] End 126,975,874 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence secondary oocyte sperm rectum bone marrow cells stromal cell of endometrium appendix lymph node spongy bone spleen Top expressed in otic placode saccule vas deferens condyle fossa medial ganglionic eminence dermis abdominal wall ureter maxillary prominence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding chromatin binding DNA topoisomerase binding DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activator activity Cellular component cytoplasm membrane chromosome condensin complex nucleus cytosol Biological process cell division cell cycle chromosome condensation mitotic chromosome condensation meiotic chromosome condensation meiotic chromosome segregation positive regulation of DNA topoisomerase (ATP-hydrolyzing) activity female meiotic nuclear division female meiosis chromosome separation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23397 215387 Ensembl ENSG00000121152 ENSMUSG00000034906 UniProt Q15003 Q8C156 RefSeq (mRNA) NM_001281710 NM_001281711 NM_001281712 NM_015341 NM_144818 RefSeq (protein) NP_001268639 NP_001268640 NP_001268641 NP_056156 NP_659067 Location (UCSC) Chr 2: 96.34 – 96.38 Mb Chr 2: 126.95 – 126.98 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Condensin complex subunit 2 also known as chromosome-associated protein H (CAP-H) or non-SMC condensin I complex subunit H (NCAPH) is a protein that in humans is encoded by the NCAPH gene. ^{[5] [6]} CAP-H is a subunit of condensin I, a large protein complex involved in chromosome condensation. Abnormal expression of NCAPH may be linked to various types of carcinogenesis as a prognostic indicator. ^[7]

Function

CAP-H is a member of the barr protein family and a regulatory subunit of the condensin complex. This complex is required for the conversion of interphase chromatin into condensed chromosomes. ^[7] CAP-H is associated with mitotic chromosomes, except during the early phase of chromosome condensation. During interphase, the protein has a distinct punctate nucleolar localization. ^[6]

Structure and interactions

NCAPH, or CAP-H Joining the terminal ends of the SMC-2 and SMC-4 heterodimer to create the condensin holocomplex.

As one of the main subunits in the highly conserved SMC condensin I complex in eukaryotes, NCAPH associates with NCAPG, NCAPD2, and the N and C termini of the SMC-4 and SMC-2 proteins. NCAPH creates a bridge between the head groups of the SMC proteins and functions as a kleisin protein. ^{[7] [8] [9]}

The interaction between NCAPH and the globular ATPase head binding sites of the C terminus and N terminus of the SMC heterodimer allows condensin to have dynamic properties. The C terminus end of NCAPH assumes a winged-helix conformation, which then associates with either head group of the SMC protein. At the opposite end of the kleisin protein, the N terminus associates with proximal coiled coil of the other SMC protein, and creates a helical bundle. ^[8] This attribute enables the condensin complex to have open and closed conformations in order to associate with chromatin and aid in proper folding of DNA in the condensation process. ^{[9] [10]}

Studies suggest that the sub-complex formed between NCAPH and NCAPG is critical for interactions with single-stranded DNA and double-stranded DNA to assist mitotic chromosome assembly in eukaryotes. ^[9]

Model organisms

Ncaph knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Recessive lethal study	Abnormal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology	Normal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Skin Histopathology	Normal
Salmonella infection	Abnormal [11]
Citrobacter infection	Normal [12]
All tests and analysis from [13] [14]

Model organisms have been used in the study of NCAPH function. A conditional knockout mouse line, called Ncaph^{tm1a(EUCOMM)Wtsi [15] [16]} was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. ^{[17] [18] [19]}

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. ^{[13] [20]} Twenty four tests were carried out on mutant mice and three significant abnormalities were observed. ^[13] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and an increased susceptibility to bacterial infection was observed in male animals. ^[13]

Clinical significance

NCAPH may be used as a prognostic indicator of carcinogenesis in humans, as the abnormal over-expression of NCAPH is observed in many cancer types. ^[21]

Studies show that, in prostate cancer, ^[22] nasopharyngeal carcinoma, ^[23] hepatocellular carcinoma, ^[24] and breast cancers, ^[25] NCAPH is commonly over-expressed, and may be used as a biomarker for various cancer types and a viable prognostic factor for identification and potential drug targeting. ^[22]

In colon cancer, NCAPH is shown to be higher expressed in cancerous cells compared to non-cancerous epithelial cells. supplementally, when NCAPH is depleted, studies show a decrease in colon cancer cell proliferation. ^{[21] [26]}  Studies show that high expression of NCAPH in colon cancer and non-small cell lung cancer patients had an increased survival rate than those with a lower expression of NCAPH. ^[26]

References

1. GRCh38: Ensembl release 89: ENSG00000121152 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000034906 - Ensembl, May 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.
5. Cabello OA, Baldini A, Bhat M, Bellen H, Belmont JW (December 1997). "Localization of BRRN1, the human homologue of Drosophila barr, to 2q11.2". Genomics. 46 (2): 311–313. doi:10.1006/geno.1997.5021. PMID   9417923.
6. "Entrez Gene: NCAPH non-SMC condensin I complex, subunit H".
7. Cui F, Hu J, Xu Z, Tan J, Tang H (June 2019). "Overexpression of NCAPH is upregulated and predicts a poor prognosis in prostate cancer". Oncology Letters. 17 (6): 5768–5776. doi:10.3892/ol.2019.10260. PMC   6507296 . PMID   31186803.
8. Palecek JJ, Gruber S (December 2015). "Kite Proteins: a Superfamily of SMC/Kleisin Partners Conserved Across Bacteria, Archaea, and Eukaryotes". Structure. 23 (12): 2183–2190. doi: 10.1016/j.str.2015.10.004 . PMID   26585514.
9. Hara K, Kinoshita K, Migita T, Murakami K, Shimizu K, Takeuchi K, et al. (May 2019). "Structural basis of HEAT-kleisin interactions in the human condensin I subcomplex". EMBO Reports. 20 (5). doi:10.15252/embr.201847183. PMC   6501013 . PMID   30858338.
10. Palecek JJ, Gruber S (December 2015). "Kite Proteins: a Superfamily of SMC/Kleisin Partners Conserved Across Bacteria, Archaea, and Eukaryotes". Structure. 23 (12): 2183–2190. doi: 10.1016/j.str.2015.10.004 . PMID   26585514.
11. "Salmonella infection data for Ncaph". Wellcome Trust Sanger Institute.
12. "Citrobacter infection data for Ncaph". Wellcome Trust Sanger Institute.
13. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID   85911512.
14. Mouse Resources Portal, Wellcome Trust Sanger Institute.
15. "International Knockout Mouse Consortium".
16. "Mouse Genome Informatics".
17. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al. (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC   3572410 . PMID   21677750.
18. Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–263. doi: 10.1038/474262a . PMID   21677718.
19. Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi: 10.1016/j.cell.2006.12.018 . PMID   17218247. S2CID   18872015.
20. van der Weyden L, White JK, Adams DJ, Logan DW (June 2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi: 10.1186/gb-2011-12-6-224 . PMC   3218837 . PMID   21722353.
21. Yin L, Jiang LP, Shen QS, Xiong QX, Zhuo X, Zhang LL, et al. (March 2017). "NCAPH plays important roles in human colon cancer". Cell Death & Disease. 8 (3): e2680. doi:10.1038/cddis.2017.88. PMC   5386579 . PMID   28300828.
22. Cui F, Hu J, Xu Z, Tan J, Tang H (June 2019). "Overexpression of NCAPH is upregulated and predicts a poor prognosis in prostate cancer". Oncology Letters. 17 (6): 5768–5776. doi:10.3892/ol.2019.10260. PMC   6507296 . PMID   31186803.
23. Xu L, Jiang Y, Zheng J, Xie G, Li J, Shi L, Fan S (July 2013). "Aberrant expression of β-catenin and E-cadherin is correlated with poor prognosis of nasopharyngeal cancer". Human Pathology. 44 (7): 1357–1364. doi:10.1016/j.humpath.2012.10.025. PMID   23375645.
24. Sun C, Huang S, Wang H, Xie R, Zhang L, Zhou Q, et al. (December 2019). "Non-SMC condensin I complex subunit H enhances proliferation, migration, and invasion of hepatocellular carcinoma". Molecular Carcinogenesis. 58 (12): 2266–2275. doi:10.1002/mc.23114. PMC   6899668 . PMID   31523845.
25. Lu H, Shi C, Wang S, Yang C, Wan X, Luo Y, et al. (October 2020). "Identification of NCAPH as a biomarker for prognosis of breast cancer". Molecular Biology Reports. 47 (10): 7831–7842. doi:10.1007/s11033-020-05859-9. PMID   33009967. S2CID   222157669.
26. Xiong Q, Fan S, Duan L, Liu B, Jiang X, Chen X, et al. (October 2020). "NCAPH is negatively associated with Mcl‑1 in non‑small cell lung cancer". Molecular Medicine Reports. 22 (4): 2916–2924. doi:10.3892/mmr.2020.11359. PMC   7453632 . PMID   32945371.

Further reading

• Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, et al. (1995). "Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1". DNA Research. 1 (5): 223–229. doi: 10.1093/dnares/1.5.223 . PMID   7584044.
• Hirano T, Kobayashi R, Hirano M (May 1997). "Condensins, chromosome condensation protein complexes containing XCAP-C, XCAP-E and a Xenopus homolog of the Drosophila Barren protein". Cell. 89 (4): 511–521. doi: 10.1016/S0092-8674(00)80233-0 . PMID   9160743. S2CID   15061740.
• Kimura K, Cuvier O, Hirano T (February 2001). "Chromosome condensation by a human condensin complex in Xenopus egg extracts". The Journal of Biological Chemistry. 276 (8): 5417–5420. doi: 10.1074/jbc.C000873200 . PMID   11136719.
• Cabello OA, Eliseeva E, He WG, Youssoufian H, Plon SE, Brinkley BR, Belmont JW (November 2001). "Cell cycle-dependent expression and nucleolar localization of hCAP-H". Molecular Biology of the Cell. 12 (11): 3527–3537. doi:10.1091/mbc.12.11.3527. PMC   60273 . PMID   11694586.
• Heale JT, Ball AR, Schmiesing JA, Kim JS, Kong X, Zhou S, et al. (March 2006). "Condensin I interacts with the PARP-1-XRCC1 complex and functions in DNA single-strand break repair". Molecular Cell. 21 (6): 837–848. doi:10.1016/j.molcel.2006.01.036. PMC   7115950 . PMID   16543152.
• Nousiainen M, Silljé HH, Sauer G, Nigg EA, Körner R (April 2006). "Phosphoproteome analysis of the human mitotic spindle". Proceedings of the National Academy of Sciences of the United States of America. 103 (14): 5391–5396. Bibcode:2006PNAS..103.5391N. doi: 10.1073/pnas.0507066103 . PMC   1459365 . PMID   16565220.
• Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (October 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology. 24 (10): 1285–1292. doi:10.1038/nbt1240. PMID   16964243. S2CID   14294292.