HGNC Approved Gene Symbol: RNF4
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38): 4:2,469,106-2,515,857 (from NCBI)
RNF4 is a SUMO (see 601912)-dependent ubiquitin E3 ligase. It has a role in DNA demethylation and is required for efficient base excision repair and maintenance of genome stability (summary by Hu et al., 2010).
The RING finger motif is a specialized zinc finger domain found in many transcriptional regulatory proteins. During analysis of 'self-positive' clones isolated during a 2-hybrid screen, Chiariotti et al. (1998) identified a novel mouse sequence containing a RING finger motif. The corresponding full-length human cDNA encodes a 190-amino acid polypeptide containing a canonical RING finger motif and 2 putative nuclear localization signals. The observed size of the in vitro-translated protein was 31 kD, in contrast with the predicted molecular mass of 21.3 kD. Northern blot analysis detected a 3-kb mRNA that was highly expressed in testis, with lower expression in all other adult human tissues tested.
Hu et al. (2010) stated that RNF4 contains 4 N-terminal SUMO-interacting motifs and a C-terminal RING finger motif critical for ubiquitination activity.
In acute promyelocytic leukemia (APL; 612376), the RARA (180240) gene is almost always fused with the PML gene (102578). APL can be treated effectively with arsenic, which induces conjugation of the small protein modifier SUMO (see SUMO2; 603042) to PML, leading to ubiquitination and proteasomal degradation of PML and the PML-RARA fusion protein. Using RNA interference, Tatham et al. (2008) demonstrated that RNF4 was required for arsenic-induced degradation of PML. RNF4 ubiquitinated PML only when PML was conjugated by SUMO2. In vitro binding studies showed that rat Rnf4 predominantly bound poly-SUMO2, and this binding was mediated by 4 conserved tandem SUMO-interaction motifs (SIMs) in the N-terminal region of Rnf4. Knockdown of RNF4 in HeLa cells resulted in the failure of arsenic to induce PML degradation and the accumulation of SUMO-modified PML in the nucleus. Tatham et al. (2008) concluded that RNF4 is a SUMO-specific E3 ubiquitin ligase.
Using mouse and human expression cDNA libraries to identify clones encoding DNA demethylases, Hu et al. (2010) identified RNF4. RNF4 increased expression of several methylated test plasmids upon transfection in human cell lines. Demethylation was independent of DNA replication and cell proliferation. The endogenous base excision repair enzymes TDG (601423) and APE1 (107748) interacted with RNF4 in HEK293 cells. Knockdown of either TDG or APE1 in HEK293 cells abrogated RNF4-mediated demethylation of methylated test plasmids. Conversely, RNF4 overexpression significantly increased enzymatic activities of both TDG and APE1 and increased their G:T mismatch repair efficiency. Hu et al. (2010) concluded that RNF4 may function as a scaffold to bring together the base excision repair enzymes for efficient DNA repair.
Chiariotti et al. (1998) determined that the RNF4 gene consists of 8 exons spanning approximately 47 kb.
By genomic sequence analysis, Chiariotti et al. (1998) found that RNF4 is part of the well-characterized region of chromosome 4 near the HTT gene (613004). The RNF4 gene was localized to chromosome 4p16.3, approximately 500 kb telomeric of HTT.
Hu et al. (2010) found that knockout of Rnf4 in mice was embryonic lethal. Rnf4 -/- embryos were stunted, failed to develop, and showed ventricular septal defects and cardiac insufficiency at death between embryonic days 14 and 15. Examination of Rnf4 -/- embryonic fibroblasts revealed global DNA hypermethylation and elevated DNA damage. Rnf4 +/- animals showed no obvious phenotype.
Chiariotti, L., Benvenuto, G., Fedele, M., Santoro, M., Simeone, A., Fusco, A., Bruni, C. B. Identification and characterization of a novel RING-finger gene (RNF4) mapping at 4p16.3. Genomics 47: 258-265, 1998. [PubMed: 9479498] [Full Text: https://doi.org/10.1006/geno.1997.5105]
Hu, X. V., Rodrigues, T. M. A., Tao, H., Baker, R. K., Miraglia, L., Orth, A. P., Lyons, G. E., Schultz, P. G., Wu, X. Identification of RING finger protein 4 (RNF4) as a modulator of DNA demethylation through a functional genomics screen. Proc. Nat. Acad. Sci. 107: 15087-15092, 2010. [PubMed: 20696907] [Full Text: https://doi.org/10.1073/pnas.1009025107]
Tatham, M. H., Geoffroy, M.-C., Shen, L., Plechanovova, A., Hattersley, N., Jaffray, E. G., Palvimo, J. J., Hay, R. T. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nature Cell Biol. 10: 538-546, 2008. [PubMed: 18408734] [Full Text: https://doi.org/10.1038/ncb1716]