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Gene Review

RAD18  -  RAD18 E3 ubiquitin protein ligase

Homo sapiens

Synonyms: E3 ubiquitin-protein ligase RAD18, Postreplication repair protein RAD18, RING finger protein 73, RNF73, hHR18, ...


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Disease relevance of RAD18

  • However, such hypersensitivity to CPT observed with RAD18-/- cells was limited to only the S phase due to the absence of the RAD18 S phase-specific function [1].
  • We observed that co-expression of human Rad18 induced the accumulation of an otherwise unstable form of HIV-1 integrase [2].
  • RAD18(-/-) cells also showed higher levels of H2AX phosphorylation and chromosomal aberrations, particularly chromosomal gaps and breaks, upon exposure to CPT [3].
  • Rad18 is necessary for functional interactions between FANCD2, BRCA2, and Rad51 to repair lesions caused by Topoisomerase-1 poisons [4]

High impact information on RAD18

  • Additionally, studies of a PCNA mutant defective for functional interactions with Polzeta, but not for monoubiquitination by the Rad6/Rad18 complex demonstrate a role for PCNA in regulating the mutagenic activity of Polzeta separate from its modification at Lys164 [5].
  • By inactivation of Rad18 in the DT40 B cell line, we show that the Rad6 pathway is involved in somatic hypermutation in these cells [6].
  • Dysfunction of human Rad18 results in defective postreplication repair and hypersensitivity to multiple mutagens [7].
  • RAD18 is an E3 ubiquitin ligase that catalyzes the monoubiquitination of PCNA, a modification central to DNA damage bypass and postreplication repair in both yeast and vertebrates [8].
  • Together, these data suggest that homologous recombination is toxic in the absence of RAD18 and show that, in addition to its established role in postreplication repair, RAD18 is also required for the orderly completion of gene conversion [8].

Biological context of RAD18

  • These data indicate that RAD18 responds to DNA damage in two distinct ways, one replication-dependent and one replication-independent, involving the SAP and zinc finger motifs, respectively [9].
  • The accumulation of RAD18 at DNA damage is observed even when DNA replication is inhibited, and a small region containing a zinc finger motif located in the middle of RAD18 is essential and sufficient for the replication-independent damage accumulation [9].
  • The human RAD18 gene codes for a protein of 484 amino acid residues with a calculated molecular weight of 54 804 Da, and the gene is localized to chromosome 3 between reference intervals D3S3591 and D3S1283 [10].
  • Enhanced genomic instability and defective postreplication repair in RAD18 knockout mouse embryonic stem cells [11].
  • However, active RAD18 is required for optimal cell survival, indicating that the lesions also block replication forks, eliciting post-replication-repair-like responses [12].

Anatomical context of RAD18

  • We found that the RAD18 transcript is expressed ubiquitously in various tissues and very highly in the testis in mammals [13].
  • Here, we report the construction of RAD18-knockout mouse embryonic stem cells by gene targeting [11].
  • To further examine Poleta functions and the mechanisms that regulate this important protein, Poleta complexes were purified from HeLa cells over-expressing epitope-tagged Poleta, and polypeptides associated with Poleta, including Rad18, Rad6 and Rev1, were identified by a combination of mass spectrometry and Western blot analysis [14].
  • Rad18 protein is required for mono-ubiquitination of PCNA and trans-lesion synthesis during DNA lesion bypass in eukaryotic cells but it remains unknown how it is activated after DNA damage [15].
  • To examine the functional relationship between WRNIP1 and Rad18 in higher eukaryotic cells, we generated WRNIP1(-/-/-)/RAD18(-/-) lines from chicken DT40 cells and compared them with single mutant cell lines [16].

Associations of RAD18 with chemical compounds

  • However, gamma-H2AX could be detected in some cells treated with methyl methanesulfonate which accumulated RAD18 protein at stalled replication sites [17].
  • Rad18 self-associates, and this interaction was abolished by replacing one of the conserved cysteine residues with phenylalanine in the zinc finger domain (C207F) [18].
  • In addition, rad9 rad18 is no more sensitive to MMS than the rad18 single mutant, suggesting that rad9 plays a role within the PRR pathway [19].
  • We show here that both S. pombe and human Smc5 and -6 interact through their hinge domains and that four independent temperature-sensitive mutants of Rad18 (Smc6) are all mutated at the same glycine residue in the hinge region [20].

Physical interactions of RAD18


Other interactions of RAD18

  • Human RAD18 is involved in S phase-specific single-strand break repair without PCNA monoubiquitination [1].
  • Thus, through interaction and complex formation with HHR6A and HHR6B, RAD18 protein may play an important role in lesion bypass mechanisms in humans [10].
  • Furthermore, the defective SSBR observed in S phase of RAD18-/- cells was also demonstrated by alkaline comet assay [1].
  • We demonstrate here that the human RAD18 is also present in the ZNF198/HHR6 protein complex, although it does not coimmunoprecipitate with the fusion kinase [22].
  • Early immobilization of nuclease FEN1 and accumulation of hRAD18 protein at stalled DNA replication forks in mammalian cells [23].

Analytical, diagnostic and therapeutic context of RAD18

  • Here we show that Rad18 protein was detected in human cells as two major bands at 75 and 85 kDa by Western blot [18].
  • These nuclear dots disperse rapidly in the nucleoplasm after treatments with various genotoxic agents, resulting in an enhancement of the intranuclear Rad18 concentration of the diffused form [13].


  1. Human RAD18 is involved in S phase-specific single-strand break repair without PCNA monoubiquitination. Shiomi, N., Mori, M., Tsuji, H., Imai, T., Inoue, H., Tateishi, S., Yamaizumi, M., Shiomi, T. Nucleic Acids Res. (2007) [Pubmed]
  2. Interaction of HIV-1 integrase with DNA repair protein hRad18. Mulder, L.C., Chakrabarti, L.A., Muesing, M.A. J. Biol. Chem. (2002) [Pubmed]
  3. A novel Rad18 function involved in protection of the vertebrate genome after exposure to camptothecin. Yoshimura, A., Nishino, K., Takezawa, J., Tada, S., Kobayashi, T., Sonoda, E., Kawamoto, T., Takeda, S., Ishii, Y., Yamada, K., Enomoto, T., Seki, M. DNA Repair (Amst.) (2006) [Pubmed]
  4. Rad18 is required for functional interactions between FANCD2, BRCA2, and Rad51 to repair DNA topoisomerase 1-poisons induced lesions and promote fork recovery. Tripathi, K., Mani, C., Clark, D.W., Palle, K. Oncotarget. (2016) [Pubmed]
  5. A novel function of DNA polymerase zeta regulated by PCNA. Northam, M.R., Garg, P., Baitin, D.M., Burgers, P.M., Shcherbakova, P.V. EMBO J. (2006) [Pubmed]
  6. Involvement of Rad18 in somatic hypermutation. Bachl, J., Ertongur, I., Jungnickel, B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Dysfunction of human Rad18 results in defective postreplication repair and hypersensitivity to multiple mutagens. Tateishi, S., Sakuraba, Y., Masuyama, S., Inoue, H., Yamaizumi, M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  8. Role for RAD18 in Homologous Recombination in DT40 Cells. Sz??ts, D., Simpson, L.J., Kabani, S., Yamazoe, M., Sale, J.E. Mol. Cell. Biol. (2006) [Pubmed]
  9. Replication-dependent and -independent Responses of RAD18 to DNA Damage in Human Cells. Nakajima, S., Lan, L., Kanno, S., Usami, N., Kobayashi, K., Mori, M., Shiomi, T., Yasui, A. J. Biol. Chem. (2006) [Pubmed]
  10. The human RAD18 gene product interacts with HHR6A and HHR6B. Xin, H., Lin, W., Sumanasekera, W., Zhang, Y., Wu, X., Wang, Z. Nucleic Acids Res. (2000) [Pubmed]
  11. Enhanced genomic instability and defective postreplication repair in RAD18 knockout mouse embryonic stem cells. Tateishi, S., Niwa, H., Miyazaki, J., Fujimoto, S., Inoue, H., Yamaizumi, M. Mol. Cell. Biol. (2003) [Pubmed]
  12. Anti-tumour compounds illudin S and Irofulven induce DNA lesions ignored by global repair and exclusively processed by transcription- and replication-coupled repair pathways. Jaspers, N.G., Raams, A., Kelner, M.J., Ng, J.M., Yamashita, Y.M., Takeda, S., McMorris, T.C., Hoeijmakers, J.H. DNA Repair (Amst.) (2002) [Pubmed]
  13. Regulated expression and dynamic changes in subnuclear localization of mammalian Rad18 under normal and genotoxic conditions. Masuyama, S., Tateishi, S., Yomogida, K., Nishimune, Y., Suzuki, K., Sakuraba, Y., Inoue, H., Ogawa, M., Yamaizumi, M. Genes Cells (2005) [Pubmed]
  14. A human DNA polymerase eta complex containing Rad18, Rad6 and Rev1; proteomic analysis and targeting of the complex to the chromatin-bound fraction of cells undergoing replication fork arrest. Yuasa, M.S., Masutani, C., Hirano, A., Cohn, M.A., Yamaizumi, M., Nakatani, Y., Hanaoka, F. Genes Cells (2006) [Pubmed]
  15. DNA damage-induced accumulation of Rad18 protein at stalled replication forks in mammalian cells involves upstream protein phosphorylation. Nikiforov, A., Svetlova, M., Solovjeva, L., Sasina, L., Siino, J., Nazarov, I., Bradbury, M., Tomilin, N. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  16. Functional Relationships between Rad18 and WRNIP1 in Vertebrate Cells. Yoshimura, A., Seki, M., Hayashi, T., Kusa, Y., Tada, S., Ishii, Y., Enomoto, T. Biol. Pharm. Bull. (2006) [Pubmed]
  17. Dephosphorylation of histone gamma-H2AX during repair of DNA double-strand breaks in mammalian cells and its inhibition by calyculin A. Nazarov, I.B., Smirnova, A.N., Krutilina, R.I., Svetlova, M.P., Solovjeva, L.V., Nikiforov, A.A., Oei, S.L., Zalenskaya, I.A., Yau, P.M., Bradbury, E.M., Tomilin, N.V. Radiat. Res. (2003) [Pubmed]
  18. Differential regulation of Rad18 through Rad6-dependent mono- and polyubiquitination. Miyase, S., Tateishi, S., Watanabe, K., Tomita, K., Suzuki, K., Inoue, H., Yamaizumi, M. J. Biol. Chem. (2005) [Pubmed]
  19. DNA damage checkpoints are involved in postreplication repair. Barbour, L., Ball, L.G., Zhang, K., Xiao, W. Genetics (2006) [Pubmed]
  20. Composition and architecture of the Schizosaccharomyces pombe Rad18 (Smc5-6) complex. Sergeant, J., Taylor, E., Palecek, J., Fousteri, M., Andrews, E.A., Sweeney, S., Shinagawa, H., Watts, F.Z., Lehmann, A.R. Mol. Cell. Biol. (2005) [Pubmed]
  21. BRCTx is a novel, highly conserved RAD18-interacting protein. Adams, D.J., van der Weyden, L., Gergely, F.V., Arends, M.J., Ng, B.L., Tannahill, D., Kanaar, R., Markus, A., Morris, B.J., Bradley, A. Mol. Cell. Biol. (2005) [Pubmed]
  22. ZNF198 protein, involved in rearrangement in myeloproliferative disease, forms complexes with the DNA repair-associated HHR6A/6B and RAD18 proteins. Kunapuli, P., Somerville, R., Still, I.H., Cowell, J.K. Oncogene (2003) [Pubmed]
  23. Early immobilization of nuclease FEN1 and accumulation of hRAD18 protein at stalled DNA replication forks in mammalian cells. Nikiforov, A.A., Sasina, L.K., Svetlova, M.P., Solovjeva, L.V., Oei, S.L., Bradbury, E.M., Tomilin, N.V. Dokl. Biochem. Biophys. (2003) [Pubmed]
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