Alternative titles; symbols
HGNC Approved Gene Symbol: RING1
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:33,208,500-33,212,716 (from NCBI)
The RING finger motif is a specialized zinc finger domain found in many transcriptional regulatory proteins. This motif was defined by Lovering et al. (1993) in their characterization of the human RING1 gene. Lovering et al. (1993) identified and cloned the RING1 gene based on its location within the human major histocompatibility complex (MHC) class II region (syntenic to the mouse t complex) on chromosome 6p21.3. The sequence of RING1 predicts a 377-amino acid polypeptide with a glycine-rich region and an N-terminal cysteine-rich domain containing a putative nuclear localization signal. Northern blot analysis showed that the gene is expressed as a 1.6-kb transcript in a variety of cell lines.
While screening for proteins that interact with the polycomb group (PcG) protein BMI1 (164831), Satijn et al. (1997) isolated the RING1 protein.
Lovering et al. (1993) showed that the RING finger domain of RING1 was able to bind zinc with tetrahedral coordination, as well as DNA.
Satijn et al. (1997) showed that RING1 binds to and colocalizes with BMI and that RING1 can act as a transcriptional repressor.
Wang et al. (2004) showed that an E3 ubiquitin ligase complex, which they designated Polycomb repressive complex-1-like (PRC1L), specifically monoubiquitinates histone-2A (H2A; see 142711) at lys119. They found that PRC1L is composed of several PcG proteins, including RING1, RNF2 (608985), BMI1, and HPH2 (EDR2; 602979). Reduction of RNF2 expression resulted in a dramatic decrease in the level of ubiquitinated H2A in HeLa cells. Wang et al. (2004) proposed that H2A ubiquitination is linked to Polycomb silencing.
De Napoles et al. (2004) found that the PRC1 proteins Mel18 (600346) and Ring1B (RNF2) were transiently enriched on inactive X chromosomes (Xi) during early mouse development. Xi was also highly enriched in ubiquitylated H2A (uH2A), and this occurred coincident with PRC1 recruitment. Analysis of cells lacking Ring1b and Ring1a proteins demonstrated that Ring1b is required to maintain global uH2A levels in embryonic stem cells and that Ring1a and Ring1b have an overlapping function in maintaining uH2A on Xi in differentiated cells.
Yokobayashi et al. (2013) identified gene dosage-dependent roles in primordial germ cell (PGC) development for Ring1 and Rnf2, 2 central components of PRC1. Both paralogs are essential for PGC development between days 10.5 and 11.5 of gestation. Rnf2 is subsequently required in female PGCs to maintain high levels of Oct4 (164177) and Nanog (607937) expression and to prevent premature induction of meiotic gene expression and entry into meiotic prophase. Chemical inhibition of retinoic acid signaling partially suppresses precocious Oct4 downregulation and Stra8 (609987) activation in Rnf2-deficient female PGCs. Chromatin immunoprecipitation analyses showed that Stra8 is a direct target of PRC1 and PRC2 in PGCs. Yokobayashi et al. (2013) concluded that their data demonstrated the importance of PRC1 gene dosage in PGC development and in coordinating the timing of sex differentiation of female PGCs by antagonizing extrinsic retinoic acid signaling.
Kikuti et al. (1997) reported that the RING1 gene contains 5 exons spanning 3 kb.
Lovering et al. (1993) mapped the RING1 gene within the MHC class II region (syntenic to the mouse t complex) on chromosome 6p21.3.
Kikuti et al. (1997) examined YAC clone Y42, which contains the MHC class II region. This region has a relatively high gene density. They identified the following human genes (in order from centromere toward telomere): HSET (603763)--HKE1.5--HKE2--HKE3--RING1--HKE6 (601417)--HKE4 (601416)--RXRB (180246)--COL11A2 (120290)--DPB2.
Associations Pending Confirmation
For discussion of a possible association between variation in the RING1 gene and a neurodevelopmental disorder with psychiatric features, see 602045.0001.
This variant is classified as a variant of unknown significance because its contribution to a neurodevelopmental disorder with psychiatric features has not been confirmed.
In a 13-year-old girl with a neurodevelopmental disorder with psychiatric features, Pierce et al. (2018) identified a de novo heterozygous c.284G-A transition (c.284G-A, NM_002931.3) in the RING1 gene, resulting in an arg95-to-gln (R95Q) substitution at a conserved residue in the catalytic domain. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies demonstrated that the mutation disrupted the ubiquitylation of histone H2A in nucleosomes, although RING1 catalytic activity was normal. Patient cells also showed decreased ubiquitylated histone H2A compared to controls. Expression of the orthologous mutation in C. elegans (spat3 gene) similarly reduced the ubiquitylation of H2A and caused neuronal migration and axonal guidance defects. The patient had intrauterine growth retardation, poor overall growth with microcephaly (-4.2 SD), and onset of developmental delay at about 1 year of age. At age 13 years, she demonstrated psychotic symptoms, including hearing voices, belief she was being poisoned, and confused, disorganized thinking; IQ was 55 (verbal) and 63 (visual). She also developed a skin vasculitis and mild scoliosis. Brain imaging was normal. The authors noted that mutations in genes involved in chromatin remodeling and histone modifications have been associated with schizophrenia, autism, and impaired intellectual development.
de Napoles, M., Mermoud, J. E., Wakao, R., Tang, Y. A., Endoh, M., Appanah, R., Nesterova, T. B., Silva, J., Otte, A. P., Vidal, M., Koseki, H., Brockdorff, N. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell 7: 663-676, 2004. [PubMed: 15525528] [Full Text: https://doi.org/10.1016/j.devcel.2004.10.005]
Kikuti, Y. Y., Tamiya, G., Ando, A., Chen, L., Kimura, M., Ferreira, E., Tsuji, K., Trowsdale, J., Inoko, H. Physical mapping 220 kb centromeric of the human MHC and DNA sequence analysis of the 43-kb segment including the RING1, HKE6, and HKE4 genes. Genomics 42: 422-435, 1997. [PubMed: 9205114] [Full Text: https://doi.org/10.1006/geno.1997.4745]
Lovering, R., Hanson, I. M., Borden, K. L. B., Martin, S., O'Reilly, N. J., Evan, G. I., Rahman, D., Pappin, D. J. C., Trowsdale, J., Freemont, P. S. Identification and preliminary characterization of a protein motif related to the zinc finger. Proc. Nat. Acad. Sci. 90: 2112-2116, 1993. [PubMed: 7681583] [Full Text: https://doi.org/10.1073/pnas.90.6.2112]
Pierce, S. B., Stewart, M. D., Gulsuner, S., Walsh, T., Dhall, A., McClellan, J. M., Klevit, R. E., King, M.-C. De novo mutation in RING1 with epigenetic effects on neurodevelopment. Proc. Nat. Acad. Sci. 115: 1558-1563, 2018. [PubMed: 29386386] [Full Text: https://doi.org/10.1073/pnas.1721290115]
Satijn, D. P. E., Gunster, M. J., van der Vlag, J., Hamer, K. M., Schul, W., Alkema, M. J., Saurin, A. J., Freemont, P. S., van Driel, R., Otte, A. P. RING1 is associated with the polycomb group protein complex and acts as a transcriptional repressor. Molec. Cell. Biol. 17: 4105-4113, 1997. [PubMed: 9199346] [Full Text: https://doi.org/10.1128/MCB.17.7.4105]
Wang, H., Wang, L., Erdjument-Bromage, H., Vidal, M., Tempst, P., Jones, R. S., Zhang, Y. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431: 873-878, 2004. [PubMed: 15386022] [Full Text: https://doi.org/10.1038/nature02985]
Yokobayashi, S., Liang, C.-Y., Kohler, H., Nestorov, P., Liu, Z., Vidal M., van Lohuizen, M., Roloff, T. C., Peters, A. H. F. M. PRC1 coordinates timing of sexual differentiation of female primordial germ cells. Nature 495: 236-240, 2013. [PubMed: 23486062] [Full Text: https://doi.org/10.1038/nature11918]