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Gene Review

RAD6  -  E2 ubiquitin-conjugating protein RAD6

Saccharomyces cerevisiae S288c

Synonyms: PSO8, Radiation sensitivity protein 6, UBC2, Ubiquitin carrier protein UBC2, Ubiquitin-conjugating enzyme E2 2, ...


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Disease relevance of RAD6

  • Under mild heat stress conditions (37-38 degrees C) rad6 null and rad6-149 mutant cells are unable to grow [1].
  • The recombinant yeast RAD6 and CDC34 gene products were expressed in Escherichia coli extracts and purified to apparent homogeneity [2].
  • This pattern of Rad6 protein expression/localization is not restricted to breast cancer cell lines, because human breast carcinomas display similar patterns of Rad6 up-regulation and nuclear localization suggesting that deregulation in expression of Rad6 may be an important step in transformation to malignant phenotype [3].
  • Metabolic suppressors of trimethoprim and ultraviolet light sensitivities of Saccharomyces cerevisiae rad6 mutants [4].
  • Overexpression of Rad6 in ovarian cancer promotes stem cell characteristics and resistance to platinum drugs  [5] .
  • Novel small molecule inhibitors of Rad6 have anticancer activity [6].

High impact information on RAD6

  • The RAD6 pathway is central to post-replicative DNA repair in eukaryotic cells; however, the machinery and its regulation remain poorly understood [7].
  • We also show that an H2B-K123R mutation perturbs silencing at the telomere, providing functional links between Rad6-mediated H2B (Lys 123) ubiquitination, Set1-mediated H3 (Lys 4) methylation, and transcriptional silencing [8].
  • Here we show that the ubiquitin-conjugating enzyme Rad6 (Ubc2) mediates methylation of histone H3 at lysine 4 (Lys 4) through ubiquitination of H2B at Lys 123 in yeast (Saccharomyces cerevisiae) [8].
  • The yeast DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme [9].
  • The RAD6 gene of the yeast Saccharomyces cerevisiae is required for a variety of cellular functions including DNA repair [9].

Biological context of RAD6

  • In addition to the tail, the cell cycle function exhibited by the chimera and CDC34 is probably dependent on a conserved region of the catalytic domain that is shared by both RAD6 and CDC34 [10].
  • Saccharomyces cerevisiae MGS1 is essential in strains deficient in the RAD6-dependent DNA damage tolerance pathway [11].
  • Despite this similarity, the CDC34 catalytic domain cannot substitute for the DNA repair and growth functions of the RAD6 catalytic domain, indicating that although these domains are structurally related, sufficient differences exist to maintain their functional individuality [10].
  • These findings suggest that Mgs1 is essential for preventing genome instability caused by replication fork arrest in cells deficient in the RAD6 pathway and may modulate replication fork movement catalyzed by yeast polymerase delta [11].
  • The RAD6 gene of Saccharomyces cerevisiae encodes a ubiquitin-conjugating enzyme required for postreplicational repair of UV-damaged DNA and for damage-induced mutagenesis [12].

Anatomical context of RAD6


Associations of RAD6 with chemical compounds

  • The conserved proline residue of RAD6 and CDC34 is part of a turn motif common to all ubiquitin-conjugating enzymes [15].
  • Strains carrying mutations in either the RAD3, RAD6 or RAD52 genes were treated with increasing concentrations of 4-nitroquinoline-1-oxide (NQO) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and the DDR transcript levels were determined by Northern hybridization analysis [16].
  • Our current model suggests that the Rad6-Rad18 complex targets Poleta at DNA gaps that result from the MMR-mediated excision of adenine mispaired with 8-oxoG, allowing error-free dCMP incorporation opposite to this lesion [17].
  • We have investigated this mechanism in Saccharomyces cerevisiae, in which it is the major component of the RAD6/RAD18 pathway, by transforming an isogenic set of rad1Delta excision-defective strains with plasmids that carry a single thymine-thymine pyrimidine (6-4) pyrimidinone photoadduct in each strand at staggered positions 28 base pairs apart [18].
  • Interaction between RAD6 and RAD52 genes was epistatic for low bleomycin concentrations [19].

Physical interactions of RAD6

  • In its role in N end-dependent protein degradation, Rad6 interacts with the UBR1-encoded ubiquitin protein ligase (E3) enzyme [12].
  • Here, we show that RAD6 forms a specific complex with the product of the DNA repair gene RAD18 [20].
  • One of these patches corresponds to a binding site for both HECT and RING domain proteins, suggesting that a single substitution in the catalytic domain of RAD6 confers upon it the ability to interact with multiple ubiquitin protein ligases (E3s) [21].
  • We also show that Paf1 complex is required for the interaction of Rad6 and COMPASS with RNA polymerase II [22].

Enzymatic interactions of RAD6

  • RAD6 and E2(20k) exhibit marked specificity for the conjugation of core histones and catalyze the processive ligation of up to three ubiquitin moieties directly to such model substrates [2].

Regulatory relationships of RAD6


Other interactions of RAD6

  • Furthermore, the disruption of the BRE1 as well as substitution of the ubiquitylation site of histone H2B also reduces some DSB formation similar to the rad6 [24].
  • The rad6 and rad18 mutants are defective in both pathways, and the rev3 mutant affects only the mutagenesis pathway, but a yeast gene that is involved only in error-free postreplication repair has not been reported [25].
  • We concluded that replication through UV lesions in yeast is mediated by at least three separate Rad6-Rad18-dependent pathways, which include mutagenic translesion synthesis by Polzeta, error-free translesion synthesis by Poleta, and postreplication repair of discontinuities by a Rad5-dependent pathway [26].
  • This is most clear for the repair of adducts on the transcribed strand, where an absolute requirement for Rad6 and Rad18 was seen [27].
  • Surprisingly, the E2(14k)) sequence is markedly more similar to Saccharomyces cerevisiae RAD6 (69% identity) than to its proposed homologs UBC4/UBC5 (38% identity) [13].

Analytical, diagnostic and therapeutic context of RAD6


  1. Heat-induced cell cycle arrest of Saccharomyces cerevisiae: involvement of the RAD6/UBC2 and WSC2 genes in its reversal. Raboy, B., Marom, A., Dor, Y., Kulka, R.G. Mol. Microbiol. (1999) [Pubmed]
  2. Ubiquitin conjugation by the yeast RAD6 and CDC34 gene products. Comparison to their putative rabbit homologs, E2(20K) AND E2(32K). Haas, A.L., Reback, P.B., Chau, V. J. Biol. Chem. (1991) [Pubmed]
  3. Rad6 overexpression induces multinucleation, centrosome amplification, abnormal mitosis, aneuploidy, and transformation. Shekhar, M.P., Lyakhovich, A., Visscher, D.W., Heng, H., Kondrat, N. Cancer Res. (2002) [Pubmed]
  4. Metabolic suppressors of trimethoprim and ultraviolet light sensitivities of Saccharomyces cerevisiae rad6 mutants. Lawrence, C.W., Christensen, R.B. J. Bacteriol. (1979) [Pubmed]
  5. Rad6 upregulation promotes stem cell-like characteristics and platinum resistance in ovarian cancer. Somasagara, R.R., Tripathi, K., Spencer, S.M., Clark, D.W., Barnett, R., Bachaboina, L., Scalici, J., Rocconi, R.P., Piazza, G.A., Palle, K. Biochem. Biophys. Res. Commun. (2016) [Pubmed]
  6. Synthesis and in vitro anticancer evaluation of some 4,6-diamino-1,3,5-triazine-2-carbohydrazides as Rad6 ubiquitin conjugating enzyme inhibitors. Kothayer, H., Spencer, S.M., Tripathi, K., Westwell, A.D., Palle, K. Bioorg. Med. Chem. Lett. (2016) [Pubmed]
  7. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Hoege, C., Pfander, B., Moldovan, G.L., Pyrowolakis, G., Jentsch, S. Nature (2002) [Pubmed]
  8. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Sun, Z.W., Allis, C.D. Nature (2002) [Pubmed]
  9. The yeast DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme. Jentsch, S., McGrath, J.P., Varshavsky, A. Nature (1987) [Pubmed]
  10. A chimeric ubiquitin conjugating enzyme that combines the cell cycle properties of CDC34 (UBC3) and the DNA repair properties of RAD6 (UBC2): implications for the structure, function and evolution of the E2s. Silver, E.T., Gwozd, T.J., Ptak, C., Goebl, M., Ellison, M.J. EMBO J. (1992) [Pubmed]
  11. Saccharomyces cerevisiae MGS1 is essential in strains deficient in the RAD6-dependent DNA damage tolerance pathway. Hishida, T., Ohno, T., Iwasaki, H., Shinagawa, H. EMBO J. (2002) [Pubmed]
  12. Domains required for dimerization of yeast Rad6 ubiquitin-conjugating enzyme and Rad18 DNA binding protein. Bailly, V., Prakash, S., Prakash, L. Mol. Cell. Biol. (1997) [Pubmed]
  13. A rabbit reticulocyte ubiquitin carrier protein that supports ubiquitin-dependent proteolysis (E214k) is homologous to the yeast DNA repair gene RAD6. Wing, S.S., Dumas, F., Banville, D. J. Biol. Chem. (1992) [Pubmed]
  14. Histone ubiquitination and chromatin remodeling in mouse spermatogenesis. Baarends, W.M., Hoogerbrugge, J.W., Roest, H.P., Ooms, M., Vreeburg, J., Hoeijmakers, J.H., Grootegoed, J.A. Dev. Biol. (1999) [Pubmed]
  15. A site-directed approach for constructing temperature-sensitive ubiquitin-conjugating enzymes reveals a cell cycle function and growth function for RAD6. Ellison, K.S., Gwozd, T., Prendergast, J.A., Paterson, M.C., Ellison, M.J. J. Biol. Chem. (1991) [Pubmed]
  16. Transcriptional regulation of DNA damage responsive (DDR) genes in different rad mutant strains of Saccharomyces cerevisiae. Maga, J.A., McClanahan, T.A., McEntee, K. Mol. Gen. Genet. (1986) [Pubmed]
  17. The post-replication repair RAD18 and RAD6 genes are involved in the prevention of spontaneous mutations caused by 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae. de Padula, M., Slezak, G., Auffret van Der Kemp, P., Boiteux, S. Nucleic Acids Res. (2004) [Pubmed]
  18. The error-free component of the RAD6/RAD18 DNA damage tolerance pathway of budding yeast employs sister-strand recombination. Zhang, H., Lawrence, C.W. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. Effects of bleomycin on growth kinetics and survival of Saccharomyces cerevisiae: a model of repair pathways. Keszenman, D.J., Salvo, V.A., Nunes, E. J. Bacteriol. (1992) [Pubmed]
  20. Specific complex formation between yeast RAD6 and RAD18 proteins: a potential mechanism for targeting RAD6 ubiquitin-conjugating activity to DNA damage sites. Bailly, V., Lamb, J., Sung, P., Prakash, S., Prakash, L. Genes Dev. (1994) [Pubmed]
  21. Creation of a pluripotent ubiquitin-conjugating enzyme. Ptak, C., Gwozd, C., Huzil, J.T., Gwozd, T.J., Garen, G., Ellison, M.J. Mol. Cell. Biol. (2001) [Pubmed]
  22. The Paf1 complex is essential for histone monoubiquitination by the Rad6-Bre1 complex, which signals for histone methylation by COMPASS and Dot1p. Wood, A., Schneider, J., Dover, J., Johnston, M., Shilatifard, A. J. Biol. Chem. (2003) [Pubmed]
  23. Suppression of genetic defects within the RAD6 pathway by srs2 is specific for error-free post-replication repair but not for damage-induced mutagenesis. Broomfield, S., Xiao, W. Nucleic Acids Res. (2002) [Pubmed]
  24. Rad6-Bre1-mediated histone H2B ubiquitylation modulates the formation of double-strand breaks during meiosis. Yamashita, K., Shinohara, M., Shinohara, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  25. MMS2, encoding a ubiquitin-conjugating-enzyme-like protein, is a member of the yeast error-free postreplication repair pathway. Broomfield, S., Chow, B.L., Xiao, W. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  26. Requirement of RAD5 and MMS2 for postreplication repair of UV-damaged DNA in Saccharomyces cerevisiae. Torres-Ramos, C.A., Prakash, S., Prakash, L. Mol. Cell. Biol. (2002) [Pubmed]
  27. Saccharomyces cerevisiae RAD5 influences the excision repair of DNA minor groove adducts. Kiakos, K., Howard, T.T., Lee, M., Hartley, J.A., McHugh, P.J. J. Biol. Chem. (2002) [Pubmed]
  28. Dissection of the functions of the Saccharomyces cerevisiae RAD6 postreplicative repair group in mutagenesis and UV sensitivity. Cejka, P., Vondrejs, V., Storchová, Z. Genetics (2001) [Pubmed]
  29. The human ubiquitin carrier protein E2(Mr = 17,000) is homologous to the yeast DNA repair gene RAD6. Schneider, R., Eckerskorn, C., Lottspeich, F., Schweiger, M. EMBO J. (1990) [Pubmed]
  30. Mutant pso8-1 of Saccharomyces cerevisiae, sensitive to photoactivated psoralens, UV radiation, and chemical mutagens, contains a rad6 missense mutant allele. Rolla, H., Grey, M., Schmidt, C.L., Niegemann, E., Brendel, M., Henriques, J.A. Curr. Genet. (2002) [Pubmed]
  31. Several mammalian ubiquitin carrier proteins, but not E2(20K), are related to the 20-kDa yeast E2, RAD6. Berleth, E.S., Pickart, C.M. Biochem. Biophys. Res. Commun. (1990) [Pubmed]
  32. Bre1, an E3 ubiquitin ligase required for recruitment and substrate selection of Rad6 at a promoter. Wood, A., Krogan, N.J., Dover, J., Schneider, J., Heidt, J., Boateng, M.A., Dean, K., Golshani, A., Zhang, Y., Greenblatt, J.F., Johnston, M., Shilatifard, A. Mol. Cell (2003) [Pubmed]
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