Protein ZGRF1

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Protein ZGRF1 is a protein encoded in the human by the ZGRF1 gene also known as C4orf21, that has a weight of 236.6 kDa.[5] The ZGRF1 gene product localizes to the cell nucleus and promotes DNA repair by stimulating homologous recombination.[6] This gene shows relatively low expression in most human tissues, with increased expression in situations of chemical dependence. ZGRF1 is orthologous to nearly all eukaryotes. Functional domains of this protein link it to a series of helicases, most notably the AAA_12 and AAA_11 domains.

ZGRF1
Identifiers
AliasesZGRF1, C4orf21, zinc finger GRF-type containing 1
External IDsMGI: 1918893; HomoloGene: 34708; GeneCards: ZGRF1; OMA:ZGRF1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001099776
NM_018392
NM_138698
NM_001350397

NM_197997

RefSeq (protein)

NP_060862
NP_001337326

NP_932114

Location (UCSC)Chr 4: 112.54 – 112.64 MbChr 3: 127.35 – 127.41 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

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The entire gene is 97,663 base pairs long and has an unprocessed mRNA that is 6,740 nucleotides in length. It consists of 28 exons that encode for a 2104 amino acid protein. 12 splice variants exist for C4orf21.

 
Human chromosomal position of c4orf21 gene on the long arm of chromosome 4

Locus

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ZGRF1 is located on the fourth chromosome on the 4q25 position near the LARP7 gene. It is encoded for on the minus strand.

Homology and evolution

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Homologous domains

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ZGRF1 contains a DUF2439 domain (domain of unknown function), zf-GRF domain, and AAA_11 and an AAA_12 domain (ATPases associated with diverse cellular activities). DUF domains are involved in telomere maintenance and meiotic segregation. AAA_11 and AAA_12 contain a P-loop motif which are involved in conjugative transfer proteins. Other helicase domains are also present in c4orf21 orthologs.

Paralogs

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There are 9 moderately-related proteins in humans that are paralogous to the ATP-dependent helicase containing domains in the C-terminus of c4orf21 after the 1612th amino acid. A majority of these proteins are in the RNA helicase family. There are no known paralogs to the large N-terminal portion of the protein.

Sequence identity of helicase domain in paralogs
Paralogous Protein Protein Name Amino Acid Identity Amino Acid Similarity
UPF1 regulator of nonsense transcripts 1 32% 51%
IGHMBP2 immunoglobulin helicase μ-binding protein 2 30% 47%
MOV10 Moloney Leukemia Virus 10 30% 47%
SETX senataxin 29% 43%
ZNFX1 zinc finger, NFX1-type containing 1 28% 47%
DNA2 DNA replication ATP-dependent helicase/nuclease 26% 44%
PPARG peroxisome proliferator-activated receptor gamma 26% 43%
HELZ helicase with zinc finger domain 25% 42%
AQR intron-binding protein Aquarius 24% 48%
 
Unrooted phylogenetic tree of proteins that are paralogous to the helicase domain containing portion of c4orf21

Orthologs

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Complete orthologs of the c4orf21 gene are found in mammalia. The helicase domain containing C-terminus portion of the gene is conserved across Eukarya.

Protein

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Primary sequence

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ZGRF1 is 236.6 kDa.

 
Amino Acid composition of c4orf21

Post-translational modifications

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ZGRF1 has experimentally determined phosphorylation sites at the Y38, S137, S140, S325, and S864 positions.

 
Experimentally determined post-translational modification sites in c4orf21

Secondary structure

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A weak transmembrane domain is predicted in the TMHMM server with one loop in the C-terminus of the protein prior to the helicase core. This domain contains both ends outside of a membrane.

Tertiary domains and quaternary structure

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ZGRF1 has related structures to Upf1, a paralog. These structures have the capability to bind zinc ions and mRNA.

 
Structure of C4ORF21 based upon UPF1 model. Image colored in rainbow from N to C terminus. This structure is based upon the crystal structure of the complex between 2 human nonsense mediated decay factors, upf1 and upf2, orthorhombic form.

Function and biochemistry

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ZGRF1 is a 5’-to-3’ DNA helicase that promotes genome stability by stimulating DNA repair by homologous recombination.[6] Specifically, ZGRF1 facilitates repair of replication-blocking DNA lesions induced by agents such as mitomycin C and camptothecin. Mechanistically, ZGRF1 physically interacts with the RAD51 recombinase and stimulates strand exchange by RAD51-RAD54.

ZGRF1 shares homology in its DUF2439 domain with Saccharomyces cerevisiae Mte1[7][8][9] and Schizosaccharomyces pombe Dbl2,[10][11] which play similar roles in recombinational DNA repair.

The human paralogs to the helicase core of the ZGRF1 gene are associated with translation, transcription, nonsense-mediated mRNA decay, RNA decay, miRNA processing, RISC assembly, and pre-mRNA splicing.[12] These paralogs operate under a SPF1 RNA helicase motif.[13]

Mov10, a paralog, and probable RNA helicase is required for RNA-mediated gene silencing by the RNA-induced silencing complex (RISC). It is also required for both miRNA-mediated translational repression and miRNA-mediated cleavage of complementary mRNAs by RISC, and for RNA-directed transcription and replication of the human hepatitis delta virus (HDV). Mov10 interacts with small capped HDV RNAs derived from genomic hairpin structures that mark the initiation sites of RNA-dependent HDV RNA transcription.

Expression

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Expression is relatively low for c4orf21 compared to other proteins. Expression of c4orf21 is slightly elevated compared to its average expression in tissue in the hematopoietic and lymphatic systems, and is above average in the brain also. Lower averages exist in liver, pharynx, and skin tissue.[14]

Transcription factor interactions

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The transcriptional start site for ZGRF1 aligns best with ATF, CREB, deltaCREB, E2F, and E2F-1 transcription factor binding sites.

Interacting proteins

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C4orf21 shows predicted protein interaction with its AQR, DNA2, IGHMBP2, LOC91431, and SETX paralogs.[15]

Clinical significance

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Upon examination of variable GEO profiles, there were many related to Hepatitis and other disorders of the liver. The best correlative studies were those in relation to liver transplant failure.[16][17] ZGRF1 showed significantly increased expression in those who were nicotine dependent versus a control group of non-smokers.[17][18]

A paralog of ZGRF1 was found to inhibit HIV-1 Replication at multiple stages. Mov10 is involved in the biological processes of RNA-mediated gene silencing, transcription, transcription regulation and has hydrolase and helicase activity through ATP and RNA binding.[19]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000138658Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051278Ensembl, 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. ^ "Entrez Gene: Chromosome 4 open reading frame 21".
  6. ^ a b Brannvoll A, Xue X, Kwon Y, Kompocholi S, Simonsen AK, Viswalingam KS, et al. (July 2020). "The ZGRF1 Helicase Promotes Recombinational Repair of Replication-Blocking DNA Damage in Human Cells". Cell Reports. 32 (1): 107849. doi:10.1016/j.celrep.2020.107849. PMC 7473174. PMID 32640219.
  7. ^ Silva S, Altmannova V, Luke-Glaser S, Henriksen P, Gallina I, Yang X, et al. (March 2016). "Mte1 interacts with Mph1 and promotes crossover recombination and telomere maintenance". Genes & Development. 30 (6): 700–17. doi:10.1101/gad.276204.115. PMC 4803055. PMID 26966248.
  8. ^ Xue X, Papusha A, Choi K, Bonner JN, Kumar S, Niu H, et al. (March 2016). "Differential regulation of the anti-crossover and replication fork regression activities of Mph1 by Mte1". Genes & Development. 30 (6): 687–99. doi:10.1101/gad.276139.115. PMC 4803054. PMID 26966246.
  9. ^ Yimit A, Kim T, Anand RP, Meister S, Ou J, Haber JE, et al. (May 2016). "MTE1 Functions with MPH1 in Double-Strand Break Repair". Genetics. 203 (1): 147–57. doi:10.1534/genetics.115.185454. PMC 4858770. PMID 26920759.
  10. ^ Yu Y, Ren JY, Zhang JM, Suo F, Fang XF, Wu F, Du LL (June 2013). "A proteome-wide visual screen identifies fission yeast proteins localizing to DNA double-strand breaks". DNA Repair. 12 (6): 433–43. doi:10.1016/j.dnarep.2013.04.001. PMID 23628481.
  11. ^ Polakova S, Molnarova L, Hyppa RW, Benko Z, Misova I, Schleiffer A, et al. (June 2016). Lichten M (ed.). "Dbl2 Regulates Rad51 and DNA Joint Molecule Metabolism to Ensure Proper Meiotic Chromosome Segregation". PLOS Genetics. 12 (6): e1006102. doi:10.1371/journal.pgen.1006102. PMC 4909299. PMID 27304859.
  12. ^ Jankowsky E (Jan 2011). "RNA helicases at work: binding and rearranging". Trends in Biochemical Sciences. 36 (1): 19–29. doi:10.1016/j.tibs.2010.07.008. PMC 3017212. PMID 20813532.
  13. ^ Fairman-Williams ME, Guenther UP, Jankowsky E (Jun 2010). "SF1 and SF2 helicases: family matters". Current Opinion in Structural Biology. 20 (3): 313–24. doi:10.1016/j.sbi.2010.03.011. PMC 2916977. PMID 20456941.
  14. ^ "c4orf21". Expression Atlas. Archived from the original on July 6, 2013. Retrieved 16 May 2013.
  15. ^ Anon. "Predicted protein interactions between paralogs and c4orf21". C4orf21 Gene - GeneCards. Retrieved 16 May 2013.
  16. ^ Nissim O, Melis M, Diaz G, Kleiner DE, Tice A, Fantola G, Zamboni F, Mishra L, Farci P (2012). "Liver regeneration signature in hepatitis B virus (HBV)-associated acute liver failure identified by gene expression profiling". PLOS ONE. 7 (11): e49611. Bibcode:2012PLoSO...749611N. doi:10.1371/journal.pone.0049611. PMC 3504149. PMID 23185381.
  17. ^ a b Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A, Lee H, Zhang N, Robertson CL, Serova N, Davis S, Soboleva A (Jan 2013). "NCBI GEO: archive for functional genomics data sets--update". Nucleic Acids Research. 41 (Database issue): D991–5. doi:10.1093/nar/gks1193. PMC 3531084. PMID 23193258.
  18. ^ Philibert RA, Ryu GY, Yoon JG, Sandhu H, Hollenbeck N, Gunter T, Barkhurst A, Adams W, Madan A (Jul 2007). "Transcriptional profiling of subjects from the Iowa adoption studies". American Journal of Medical Genetics Part B. 144B (5): 683–90. doi:10.1002/ajmg.b.30512. PMID 17342724. S2CID 6002286.
  19. ^ Burdick R, Smith JL, Chaipan C, Friew Y, Chen J, Venkatachari NJ, Delviks-Frankenberry KA, Hu WS, Pathak VK (Oct 2010). "P body-associated protein Mov10 inhibits HIV-1 replication at multiple stages". Journal of Virology. 84 (19): 10241–53. doi:10.1128/JVI.00585-10. PMC 2937795. PMID 20668078.
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Further reading

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