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Gene Review

RAD50  -  RAD50 homolog (S. cerevisiae)

Homo sapiens

Synonyms: DNA repair protein RAD50, NBSLD, RAD50-2, RAD502, hRAD50, ...
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Disease relevance of RAD50


High impact information on RAD50


Biological context of RAD50


Anatomical context of RAD50

  • Nitric oxide-dependent cytoskeletal changes and inhibition of endothelial cell migration contribute to the suppression of angiogenesis by RAD50 gene transfer [13].
  • We have compared the chromatin structure of the RAD50/IL13/IL4 locus in Th2 cells and mast cells [14].
  • The multiplicity of hMre11 and hRad50 foci is much higher in the DSB repair-deficient cell line 180BR than in repair-proficient cells. hMre11-hRad50 focus formation is markedly reduced in cells derived from ataxia-telangiectasia patients, whereas hRad51 focus formation is markedly increased [15].
  • In this report, we demonstrate that the human Rad50 and Mre11 proteins are stably associated in a protein complex which may include three other proteins. hRAD50 is expressed in all tissues examined, but mRNA levels are significantly higher in the testis [16].
  • The Mre11-NLS protein complexed with Rad50, localized to the nucleus in NBS fibroblasts, and associated with chromatin [17].

Associations of RAD50 with chemical compounds

  • Expression of hRAD50 partially rescued the MMS (methyl methanesulfonate)-sensitive phenotype in rad50 mutant yeast, whereas hRAD50-3 did not show complementation [18].
  • A detailed examination of the involvement of the DNA repair pathway following Vorinostat treatment showed that Vorinostat reduced the expression of the repair-related genes Ku70, Ku80, and Rad50 in A375 cells as detected by Western blot analysis [19].
  • Here we present a 2.2 A crystal structure of the Rad50 coiled-coil region that reveals an unexpected dimer interface at the apex of the coiled coils in which pairs of conserved Cys-X-X-Cys motifs form interlocking hooks that bind one Zn(2+) ion [20].
  • These cytotoxic effects of overexpressed hRAD50 in HeLa, SaOS-2, and HCT116 p21(+/+) cells were partially blocked by pretreatment of cells with N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a pan-caspase inhibitor [11].
  • We established tetracycline-regulated, stable hRAD50 expression systems in SaOS-2 cells, which retain mutated p53, and in HeLa cells [11].

Physical interactions of RAD50


Co-localisations of RAD50

  • At this time, a significant fraction of the gamma-H2AX nuclear foci co-localized with the foci of RAD50 protein that did not co-localize with replication sites [24].
  • In normal fibroblasts, CDKN1A foci colocalized with particle-induced foci of the hMre11 and Rad50 proteins [25].

Regulatory relationships of RAD50

  • These results are consistent with the possibility that the heat-induced perturbation in Mre11 localization and its radiation-induced association with Rad50 contributes to an increase in radiosensitivity [26].

Other interactions of RAD50

  • Such aberrations can be rescued by expression of wild-type BRCA1 as well as a mutant at the RAD50-binding domain but not at the C-terminal BRCT domain, suggesting that the C-terminal BRCT domain has a critical role in these processes [27].
  • Despite providing some partial complementation of the radiation-sensitive phenotype, the nibrin-Mre11-Rad50 complexes in these cells were unable to form foci [28].
  • Independent roles for nibrin and Mre11-Rad50 in the activation and function of Atm [29].
  • Investigation of the genetic requirements for this process have revealed that at least two different recombination pathways, defined by RAD50 and RAD51, can promote telomere maintenance [30].
  • In telomerase-null Saccharomyces cerevisiae, an analogous survivor mechanism is dependent on the RAD50 gene [31].

Analytical, diagnostic and therapeutic context of RAD50

  • Molecular cloning and characterization of splice variants of human RAD50 gene [18].
  • Biochemical, X-ray and electron microscopy data indicate that these hooks can join oppositely protruding Rad50 coiled-coil domains to form a flexible bridge of up to 1,200 A [20].
  • When the hRAD50 expression cDNA was injected intratumorally with liposomes, it regressed or delayed tumor development in the animal model and nitric oxide synthase expression was induced in the tumor tissues that had regressed [11].
  • Effect of human RAD50 gene therapy on glaucoma filtering surgery in rabbit eye [32].
  • In a recent study (Moreno-Herrero et al., 2005), atomic force microscopy (AFM) imaging of the human Mre11/Rad50/Nbs1 (MRN) complex engaging substrate DNA revealed large-scale, DNA binding-induced propagation of conformational change to the distal ends of the Rad50 coiled coils and erection of a 1000 A scaffold to productively bridge DNA ends [33].


  1. DNA cross-link-dependent RAD50/MRE11/NBS1 subnuclear assembly requires the Fanconi anemia C protein. Pichierri, P., Averbeck, D., Rosselli, F. Hum. Mol. Genet. (2002) [Pubmed]
  2. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Heikkinen, K., Rapakko, K., Karppinen, S.M., Erkko, H., Knuutila, S., Lundán, T., Mannermaa, A., Børresen-Dale, A.L., Borg, A., Barkardottir, R.B., Petrini, J., Winqvist, R. Carcinogenesis (2006) [Pubmed]
  3. Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility. Heikkinen, K., Karppinen, S.M., Soini, Y., Mäkinen, M., Winqvist, R. J. Med. Genet. (2003) [Pubmed]
  4. Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Stracker, T.H., Carson, C.T., Weitzman, M.D. Nature (2002) [Pubmed]
  5. Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Zhao, S., Weng, Y.C., Yuan, S.S., Lin, Y.T., Hsu, H.C., Lin, S.C., Gerbino, E., Song, M.H., Zdzienicka, M.Z., Gatti, R.A., Shay, J.W., Ziv, Y., Shiloh, Y., Lee, E.Y. Nature (2000) [Pubmed]
  6. Molecular characterization of inter-telomere and intra-telomere mutations in human ALT cells. Varley, H., Pickett, H.A., Foxon, J.L., Reddel, R.R., Royle, N.J. Nat. Genet. (2002) [Pubmed]
  7. New glimpses of an old machine. Paull, T.T. Cell (2001) [Pubmed]
  8. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Zhu, X.D., Küster, B., Mann, M., Petrini, J.H., de Lange, T. Nat. Genet. (2000) [Pubmed]
  9. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Stewart, G.S., Maser, R.S., Stankovic, T., Bressan, D.A., Kaplan, M.I., Jaspers, N.G., Raams, A., Byrd, P.J., Petrini, J.H., Taylor, A.M. Cell (1999) [Pubmed]
  10. MRE11/RAD50 cleaves DNA in the AID/UNG-dependent pathway of immunoglobulin gene diversification. Larson, E.D., Cummings, W.J., Bednarski, D.W., Maizels, N. Mol. Cell (2005) [Pubmed]
  11. Overexpressed human RAD50 exhibits cell death in a p21(WAF1/CIP1)-dependent manner: its potential utility in local gene therapy of tumor. Shin, B.A., Ahn, K.Y., Kook, H., Koh, J.T., Kang, I.C., Lee, H.C., Kim, K.K. Cell Growth Differ. (2001) [Pubmed]
  12. Indicators of late normal tissue response after radiotherapy for head and neck cancer: fibroblasts, lymphocytes, genetics, DNA repair, and chromosome aberrations. Borgmann, K., Röper, B., El-Awady, R., Brackrock, S., Bigalke, M., Dörk, T., Alberti, W., Dikomey, E., Dahm-Daphi, J. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. (2002) [Pubmed]
  13. Nitric oxide-dependent cytoskeletal changes and inhibition of endothelial cell migration contribute to the suppression of angiogenesis by RAD50 gene transfer. Kook, H., Ahn, K.Y., Lee, S.E., Na, H.S., Kim, K.K. FEBS Lett. (2003) [Pubmed]
  14. Regulation of gene expression in mast cells: micro-rNA expression and chromatin structural analysis of cytokine genes. Monticelli, S., Ansel, K.M., Lee, D.U., Rao, A. Novartis Found. Symp. (2005) [Pubmed]
  15. hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks. Maser, R.S., Monsen, K.J., Nelms, B.E., Petrini, J.H. Mol. Cell. Biol. (1997) [Pubmed]
  16. Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repair. Dolganov, G.M., Maser, R.S., Novikov, A., Tosto, L., Chong, S., Bressan, D.A., Petrini, J.H. Mol. Cell. Biol. (1996) [Pubmed]
  17. Active role for nibrin in the kinetics of atm activation. Cerosaletti, K., Wright, J., Concannon, P. Mol. Cell. Biol. (2006) [Pubmed]
  18. Molecular cloning and characterization of splice variants of human RAD50 gene. Kim, K.K., Shin, B.A., Seo, K.H., Kim, P.N., Koh, J.T., Kim, J.H., Park, B.R. Gene (1999) [Pubmed]
  19. Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Munshi, A., Tanaka, T., Hobbs, M.L., Tucker, S.L., Richon, V.M., Meyn, R.E. Mol. Cancer Ther. (2006) [Pubmed]
  20. The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair. Hopfner, K.P., Craig, L., Moncalian, G., Zinkel, R.A., Usui, T., Owen, B.A., Karcher, A., Henderson, B., Bodmer, J.L., McMurray, C.T., Carney, J.P., Petrini, J.H., Tainer, J.A. Nature (2002) [Pubmed]
  21. Mutations in the RAD54 recombination gene in primary cancers. Matsuda, M., Miyagawa, K., Takahashi, M., Fukuda, T., Kataoka, T., Asahara, T., Inui, H., Watatani, M., Yasutomi, M., Kamada, N., Dohi, K., Kamiya, K. Oncogene (1999) [Pubmed]
  22. MRE11/RAD50/NBS1: complex activities. Assenmacher, N., Hopfner, K.P. Chromosoma (2004) [Pubmed]
  23. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Zhong, Q., Chen, C.F., Li, S., Chen, Y., Wang, C.C., Xiao, J., Chen, P.L., Sharp, Z.D., Lee, W.H. Science (1999) [Pubmed]
  24. 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]
  25. Characterization of CDKN1A (p21) binding to sites of heavy-ion-induced damage: colocalization with proteins involved in DNA repair. Jakob, B., Scholz, M., Taucher-Scholz, G. Int. J. Radiat. Biol. (2002) [Pubmed]
  26. Radiosensitization of heat resistant human tumour cells by 1 hour at 41.1 degrees C and its effect on DNA repair. Xu, M., Myerson, R.J., Straube, W.L., Moros, E.G., Lagroye, I., Wang, L.L., Lee, J.T., Roti Roti, J.L. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. (2002) [Pubmed]
  27. Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells. Furuta, S., Jiang, X., Gu, B., Cheng, E., Chen, P.L., Lee, W.H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  28. Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization. Desai-Mehta, A., Cerosaletti, K.M., Concannon, P. Mol. Cell. Biol. (2001) [Pubmed]
  29. Independent roles for nibrin and Mre11-Rad50 in the activation and function of Atm. Cerosaletti, K., Concannon, P. J. Biol. Chem. (2004) [Pubmed]
  30. Telomere maintenance without telomerase. Lundblad, V. Oncogene (2002) [Pubmed]
  31. Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex. Jiang, W.Q., Zhong, Z.H., Henson, J.D., Neumann, A.A., Chang, A.C., Reddel, R.R. Mol. Cell. Biol. (2005) [Pubmed]
  32. Effect of human RAD50 gene therapy on glaucoma filtering surgery in rabbit eye. Yoon, K.C., Yang, K.J., Seo, J.S., Lee, S.E., Heo, T., Chun, B.J., Jung, S., Kim, K.K., Ahn, K.Y. Curr. Eye Res. (2004) [Pubmed]
  33. A nanomachine for making ends meet: MRN is a flexing scaffold for the repair of DNA double-strand breaks. Williams, R.S., Tainer, J.A. Mol. Cell (2005) [Pubmed]
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