Alternative titles; symbols
HGNC Approved Gene Symbol: RNASEH2C
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:65,717,673-65,720,798 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Aicardi-Goutieres syndrome 3 | 610329 | Autosomal recessive | 3 |
The RNASEH2C gene encodes subunit C of the human ribonuclease H2 enzyme complex which cleaves ribonucleotides from RNA:DNA duplexes. See also RNASEH2A (606034) and RNASEH2B (610326).
The RNASEH2C gene encodes a 164-amino acid protein (Crow et al., 2006).
The RNASEH2C gene contains 4 exons (Crow et al., 2006).
The RNASEH2C gene maps to chromosome 11q13.2 (Crow et al., 2006).
By transient expression in HEK293T cells, Crow et al. (2006) showed that the human RNASEH2A, RNASEH2B, and RNASEH2C genes interact with each other and form an enzymatic protein complex with RNase H2 activity. The complex was able to recognize and cleave a single ribonucleotide embedded in a DNA-DNA complex.
By expressing fluorescence-tagged RNASEH2 subunits individually or together in HeLa cells, Kind et al. (2014) determined that the B subunit was required for nuclear expression of the A and C subunits. Mutation analysis revealed that the C terminus of the C subunit, but not a catalytically active A subunit, was also required for formation of a stable nuclear complex. Ring-shaped trimeric PCNA (176740) functions as a 'sliding clamp' along DNA that guides assembly of factors involved in DNA replication and repair. PCNA recruited RNASEH2 to sites of DNA damage, and the PIP-box motif of subunit B was required for interaction of RNASEH2 with PCNA and accumulation of RNASEH2 to sites of DNA damage. In addition, a catalytically active A subunit bound more tightly than a catalytically inactive A subunit to sites of DNA replication.
Using CRISPR screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP (173870) inhibitor, Zimmermann et al. (2018) identified a high-confidence set of 73 genes that when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, Zimmermann et al. (2018) discovered that mutations in all 3 genes encoding ribonuclease H2 (RNASEH2A, RNASEH2B, and RNASEH2C) sensitized cells to PARP inhibition and established that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase-1 (TOP1; 126420), resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. Zimmermann et al. (2018) concluded that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukemia may provide an opportunity to exploit these findings therapeutically.
In affected members of 5 Pakistani families with Aicardi-Goutieres syndrome-3 (AGS3; 610329), Crow et al. (2006) identified a homozygous mutation in the RNASH2C gene (610330.0001). Haplotype analysis suggested a founder effect. Affected members of a Pakistani family carried another homozygous mutation (610330.0002).
In 2 Pakistani sisters with variable manifestations of AGS3, Vogt et al. (2013) identified homozygosity for the R69W mutation in the RNASEH2C gene. Both unaffected parents were heterozygous for the mutation.
By whole-exome sequencing in 50 children with developmental disturbances of unclear etiology and with nonspecific neurologic manifestations, Mahler et al. (2019) identified 1 child with a homozygous mutation in the RNASEH2C gene (c.205G-A; R69W). The child was described as having severe global developmental delay and regression with a movement and myelinization disorder.
Hiller et al. (2012) found that Rnaseh2c -/- mouse embryos were small at embryonic day 9.5 and were not detected thereafter. Cells lacking Rnaseh2c proliferated more slowly than control cells and accumulated in G2/M phase due to chronic activation of a DNA damage response associated with an increased frequency of single-strand breaks, increased H2ax (H2AFX; 601772) phosphorylation, and induction of p53 (TP53; 191170) target genes, particularly p21 (CDKN1A; 116899). Rnaseh2c-deficient cells showed an increased genomic ribonucleotide load, suggesting that unrepaired ribonucleotides triggered the DNA damage response in these cells. Hiller et al. (2012) concluded that RNASEH2 is essential for removal of ribonucleotides from the genome to prevent DNA damage.
In affected members of 5 consanguineous Pakistani families with Aicardi-Goutieres syndrome-3 (AGS3; 610329), Crow et al. (2006) identified a homozygous 205C-T transition in exon 2 of the RNASH2C gene, resulting in an arg69-to-trp (R69W) substitution. Haplotype analysis suggested a founder effect.
Rice et al. (2007) found this mutation on a common haplotype in 13 families of Pakistani origin.
In 2 Pakistani sisters with variable manifestations of AGS3, Vogt et al. (2013) identified homozygosity for the R69W mutation in the RNASEH2C gene. Her unaffected parents were heterozygous for the mutation.
In affected members of a consanguineous Bangladeshi family with Aicardi-Goutieres syndrome-3 (AGS3; 610329), Crow et al. (2006) identified a homozygous 428A-T transversion in exon 3 of the RNASEH2C gene, resulting in a lys143-to-ile (K143I) substitution.
Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nature Genet. 38: 910-916, 2006. [PubMed: 16845400] [Full Text: https://doi.org/10.1038/ng1842]
Hiller, B., Achleitner, M., Glage, S., Naumann, R., Behrendt, R., Roers, A. Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. J. Exp. Med. 209: 1419-1426, 2012. [PubMed: 22802351] [Full Text: https://doi.org/10.1084/jem.20120876]
Kind, B., Muster, B., Staroske, W., Herce, H. D., Sachse, R., Rapp, A., Schmidt, F., Koss, S., Cardoso, M. C., Lee-Kirsch, M. A. Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutieres syndrome. Hum. Molec. Genet. 23: 5950-5960, 2014. [PubMed: 24986920] [Full Text: https://doi.org/10.1093/hmg/ddu319]
Mahler, E. A., Johannsen, J., Tsiakas, K., Kloth, K., Luttgen, S., Muhlhausen, C., Alhaddad, B., Haack, T. B., Strom, T. M., Kortum, F., Meitinger, T., Muntau, A. C., Santer, R., Kubisch, C., Lessel, D., Denecke, J., Hempel, M. Exome sequencing in children. Dtsch. Arztebl. Int. 116: 197-204, 2019. [PubMed: 31056085] [Full Text: https://doi.org/10.3238/arztebl.2019.0197]
Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S. A., Bacino, C. A., Barroso, B., Baxter, P., Benko, W. S., and 106 others. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am. J. Hum. Genet. 81: 713-725, 2007. [PubMed: 17846997] [Full Text: https://doi.org/10.1086/521373]
Vogt, J., Agrawal, S., Ibrahim, Z., Southwood, T. R., Philip, S., MacPherson, L., Bhole, M. V., Crow, Y. J., Oley, C. Striking intrafamilial phenotypic variability in Aicardi-Goutieres syndrome associated with the recurrent Asian founder mutation in RNASEH2C. Am. J. Med. Genet. 161A: 338-342, 2013. [PubMed: 23322642] [Full Text: https://doi.org/10.1002/ajmg.a.35712]
Zimmermann, M., Murina, O., Reijns, M. A. M., Agathanggelou, A., Challis, R., Tarnauskaite, Z., Muir, M., Fluteau, A., Aregger, M., McEwan, A., Yuan, W., Clarke, M., and 12 others. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature 559: 285-289, 2018. [PubMed: 29973717] [Full Text: https://doi.org/10.1038/s41586-018-0291-z]