ZC3HC1

The ZC3HC1 gene resides on chromosome 7 at the band 7q32.2 and includes 14 exons.

NIPA is a 60-kDa E3 ligase that contains one C3HC-type zinc finger and one F-box-like region.{{cite journal | vauthors = Ouyang T, Bai RY, Bassermann F, von Klitzing C, Klumpen S, Miething C, Morris SW, Peschel C, Duyster J | title = Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA) | journal = The Journal of Biological Chemistry | volume = 278 | issue = 32 | pages = 30028–36 | date = August 2003 | pmid = 12748172 | doi = 10.1074/jbc.M300883200 | doi-access = free }}{{cite journal | vauthors = Kunnas T, Nikkari ST | title = Association of Zinc Finger, C3HC-Type Containing 1 (ZC3HC1) rs11556924 Genetic Variant With Hypertension in a Finnish Population, the TAMRISK Study | journal = Medicine | volume = 94 | issue = 32 | pages = e1221 | date = August 2015 | pmid = 26266351 | doi = 10.1097/MD.0000000000001221 | pmc=4616712}}{{Cite web|url=https://www.uniprot.org/uniprot/Q86WB0|title=ZC3HC1 - Nuclear-interacting partner of ALK - Homo sapiens (Human) - ZC3HC1 gene & protein|website=www.uniprot.org|access-date=2016-10-11}} Moreover, a 50-residue region (amino acids 352-402) at its C-terminal serves as the nuclear translocation signal (NLS sequence) while a 96-residue region (amino acids 306-402) is proposed to serve as the phosphotyrosine-binding domain.{{cite journal | vauthors = Bassermann F, von Klitzing C, Illert AL, Münch S, Morris SW, Pagano M, Peschel C, Duyster J | title = Multisite phosphorylation of nuclear interaction partner of ALK (NIPA) at G2/M involves cyclin B1/Cdk1 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 22 | pages = 15965–72 | date = June 2007 | pmid = 17389604 | doi = 10.1074/jbc.M610819200 | doi-access = free }} NIPA is one component of the nuclear SCFNIPA complex, and phosphorylation of NIPA at three serine residues, Ser-354, Ser-359 and Ser-395, has been demonstrated to inactivate the complex as a whole.

NIPA is broadly expressed in the human tissues, with the highest expression in heart, skeletal muscle, and testis. It is a human F-box protein that defines an SCF-type ubiquitin E3 ligase, the formation of which is regulated by cell-cycle-dependent phosphorylation of NIPA. Cyclin B1, essential in the entry into mitosis, is targeted by SCFNIPA in interphase. Phosphorylation of NIPA occurs in G2 phase, results in dissociation of NIPA from the SCF core, and has been proven critical for proper G2/M transition.{{cite journal | vauthors = Bassermann F, von Klitzing C, Münch S, Bai RY, Kawaguchi H, Morris SW, Peschel C, Duyster J | title = NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry | journal = Cell | volume = 122 | issue = 1 | pages = 45–57 | date = July 2005 | pmid = 16009132 | doi = 10.1016/j.cell.2005.04.034 | s2cid = 16122567 | doi-access = free }} Oscillating ubiquitination of nuclear cyclin B1 driven by the SCFNIPA complex contributes to the timing of mitotic entry.{{cite journal | vauthors = Bassermann F, Peschel C, Duyster J | title = Mitotic entry: a matter of oscillating destruction | journal = Cell Cycle | volume = 4 | issue = 11 | pages = 1515–7 | date = November 2005 | pmid = 16258267 | doi = 10.4161/cc.4.11.2192 | doi-access = free }} NIPA is also reported to delay apoptosis and the localization of NIPA is required for this antiapoptotic function.

In humans, NIPA has been implicated in cardiovascular diseases by genome-wide association (GWAS) studies. Specifically, a single-nucleotide polymorphism (SNP) situated in ZC3HC1 has been shown to predict coronary artery disease.{{cite journal | vauthors = Jones PD, Kaiser MA, Ghaderi Najafabadi M, McVey DG, Beveridge AJ, Schofield CL, Samani NJ, Webb TR | title = The Coronary Artery Disease-associated Coding Variant in Zinc Finger C3HC-type Containing 1 (ZC3HC1) Affects Cell Cycle Regulation | journal = The Journal of Biological Chemistry | volume = 291 | issue = 31 | pages = 16318–27 | date = July 2016 | pmid = 27226629 | doi = 10.1074/jbc.M116.734020 | pmc=4965579| doi-access = free }}{{cite journal | vauthors = Jones PD, Kaiser MA, Ghaderi Najafabadi M, McVey DG, Beveridge AJ, Schofield CL, Samani NJ, Webb TR | title = The Coronary Artery Disease-associated Coding Variant in Zinc Finger C3HC-type Containing 1 (ZC3HC1) Affects Cell Cycle Regulation | journal = The Journal of Biological Chemistry | volume = 291 | issue = 31 | pages = 16318–27 | date = July 2016 | pmid = 27226629 | pmc = 4965579 | doi = 10.1074/jbc.M116.734020 | doi-access = free }} This prediction appears to be independent of traditional risk factors for cardiovascular disease such as high cholesterol levels, high blood pressure, obesity, smoking and diabetes mellitus, which are primary targets of current treatments for coronary artery disease. Therefore, studying the function of this gene may identify novel pathways contributing to coronary artery disease that result in the development of novel therapeutics.

At the coronary artery disease-associated locus 7q32.2, only a single SNP (rs11556924) is associated with coronary artery disease risk, with no other variants in strong linkage disequilibrium. The rs11556924 SNP in the ZC3HC1 gene results in an arginine-histidine polymorphism at amino acid residue 363 in NIPA.{{cite journal | pmid = 16009132 | doi=10.1016/j.cell.2005.04.034 | volume=122 | issue=1 | title=NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry | date=July 2005 | journal=Cell | pages=45–57 | vauthors=Bassermann F, von Klitzing C, Münch S et al| s2cid=16122567 | doi-access=free }} Furthermore, rs11556924 has also been associated with altered carotid intima-media thickness in patients with rheumatoid arthritis{{cite journal | vauthors = López-Mejías R, Genre F, García-Bermúdez M, Corrales A, González-Juanatey C, Llorca J, Miranda-Filloy JA, Rueda-Gotor J, Blanco R, Castañeda S, Martín J, González-Gay MA | title = The ZC3HC1 rs11556924 polymorphism is associated with increased carotid intima-media thickness in patients with rheumatoid arthritis | journal = Arthritis Research & Therapy | volume = 15 | issue = 5 | pages = R152 | date = 2013-01-01 | pmid = 24286297 | doi = 10.1186/ar4335 | pmc=3978706 | doi-access = free }} and with altered risk of atrial fibrillation.{{cite journal | vauthors = Yamase Y, Kato K, Horibe H, Ueyama C, Fujimaki T, Oguri M, Arai M, Watanabe S, Murohara T, Yamada Y | title = Association of genetic variants with atrial fibrillation | journal = Biomedical Reports | volume = 4 | issue = 2 | pages = 178–182 | date = February 2016 | pmid = 26893834 | doi = 10.3892/br.2015.551 | pmc=4734142}}

Additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the ZC3HC1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).

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Category:Genes mutated in mice