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Gene Review

RNASEL  -  ribonuclease L (2',5'-oligoisoadenylate...

Homo sapiens

Synonyms: 2-5A-dependent RNase, 2-5A-dependent ribonuclease, PRCA1, RNS4, RNase L, ...
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Disease relevance of RNASEL

  • RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases [1].
  • RNASEL germline variants are associated with pancreatic cancer [2].
  • We thus mapped the RNASEL transcriptional start site using 5'-rapid amplification of cDNA ends (5'-RACE) and primer extension methods with RNA from human histiocytic lymphoma U937 cells [3].
  • Lack of association between RNASEL Arg462Gln variant and the risk of breast cancer [4].
  • We reevaluated the role of the RNASEL 471delAAAG Ashkenazi founder mutation in 1,642 Ashkenazi patients with prostate, bladder, breast/ovarian, and colon cancers; Ashkenazi controls; and in non-Ashkenazi prostate cancer patients and controls [5].
  • This is the first study that investigates the association of prostate cancer risk with RNASEL variants in Hispanic men [6].

Psychiatry related information on RNASEL


High impact information on RNASEL


Chemical compound and disease context of RNASEL

  • A 2',5'-oligoadenylate (2-5A)-dependent 37-kDa form of RNase L has been reported in extracts of peripheral blood mononuclear cells (PBMC) from individuals with chronic fatigue syndrome (CFS) [11].
  • Phosphorothioate/phosphodiester trimer and tetramer 2-5A derivatives revealed differences in the stereodynamics of activation of RNase L and inhibition of HIV-1 replication [12].
  • Purine 8-bromination modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates. Possible influence of glycosyl torsion angle [13].

Biological context of RNASEL


Anatomical context of RNASEL

  • The known 471delAAAG truncating mutation was found in the RNASEL gene in cell line LNCaP [18].
  • An Alternative Spliced RNASEL Variant in Peripheral Blood Leukocytes [19].
  • Quantitative RT-PCR measurements of RNA from different PBL cell types separated by fluorescence activated cell sorting (FACS) showed that complete RNASEL mRNA levels were significantly elevated in granulocytes compared with all other PBL cell types, whereas expression was lowest in CD8(+) T cells [19].
  • Its expression in reticulocyte extracts antagonizes the 2-5A binding ability and the nuclease activity of endogenous RNase L or the cloned 2DR polypeptide [20].
  • We found that a fraction of cellular RNase L and RLI is localized in the mitochondria [21].

Associations of RNASEL with chemical compounds

  • Biostable phosphorothioate analogues of 2-5A were synthesized chemically and used to study the effects of naturally occurring mutations and polymorphisms in RNASEL [22].
  • Analysis of genotypes revealed that presence of the leucine ELAC2 allele (OR 1.54: 95% CI=0.99-2.41, SS vs. SL, LL) and homozygosity for the glutamic acid RNASEL allele (OR 1.68: 95% CI=1.04-2.70, EE vs. DE, DD) were associated with increased risk [23].
  • Cells deficient in RNase L, but not the control cells, were highly resistant to apoptosis by the RNase L activator, 2',5'-oligoadenylate (2-5A) [16].
  • Interferon induction of 2-5A-dependent RNAse expression was demonstrated by measuring the mRNA levels in cells treated with interferon and cycloheximide [10].
  • The first and second internucleotide linkages are critical for activation of recombinant, human RNase L; A(Rp)ApA, A(Sp)ApA and ApA(Rp)A are agonists (IC50 = 2 x 10(-7), 2 x 10(-6) and 8 x 10(-6) M); ApA(Sp)A is an antagonist [12].

Physical interactions of RNASEL

  • Likewise RLI is coimmunoprecipitated with the RNase L complex by a nuclease-specific antibody [20].
  • We identify and characterize the human translation termination factor eRF3/GSPT1 as an interacting partner of RNase L [24].
  • The cells were returned to monolayer growth for 18 h, and then harvested and assayed to determine the amount of RNase L protein (via [32P]2-5A binding) and the specific activities of RNase L and 2-5A synthetase [25].
  • It was also found that the crystal structure of the ankyrin repeat domain L.2-5A complex accurately portrays the 2-5A binding mode in full-length RNase L [26].

Enzymatic interactions of RNASEL


Regulatory relationships of RNASEL


Other interactions of RNASEL

  • CONCLUSIONS: These results suggest that, in a European-American population, ELAC2 217L and RNASEL 541E are associated with metastatic sporadic disease [23].
  • Several putative prostate cancer candidate genes have also been identified including RNASEL, MSR1, and ELAC2 [32].
  • Surprisingly, the RNase L-deficient cells were also highly resistant to apoptosis by combination treatments with a topoisomerase (Topo) I inhibitor (camptothecin, topotecan, or SN-38) and tumor necrosis factor-related apoptosis-inducing ligand [TRAIL (Apo2L)] [16].
  • RLI does not lead to 2-5A degradation or to irreversible modification of RNase L [20].
  • Susceptibility to WNV disease in inbred strains of mice was mapped to a nonsense mutation in the gene encoding the 1b isoform of 2'-5'-oligoadenylate synthetase (OAS), a member of the OAS/RNase L system of innate viral resistance [33].
  • Immunoprecipitation demonstrated that RNase-L mRNA associates with a HuR containing complex in intact cells [34].

Analytical, diagnostic and therapeutic context of RNASEL


  1. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Casey, G., Neville, P.J., Plummer, S.J., Xiang, Y., Krumroy, L.M., Klein, E.A., Catalona, W.J., Nupponen, N., Carpten, J.D., Trent, J.M., Silverman, R.H., Witte, J.S. Nat. Genet. (2002) [Pubmed]
  2. RNASEL germline variants are associated with pancreatic cancer. Bartsch, D.K., Fendrich, V., Slater, E.P., Sina-Frey, M., Rieder, H., Greenhalf, W., Chaloupka, B., Hahn, S.A., Neoptolemos, J.P., Kress, R. Int. J. Cancer (2005) [Pubmed]
  3. Mapping of the human RNASEL promoter and expression in cancer and normal cells. Zhou, A., Molinaro, R.J., Malathi, K., Silverman, R.H. J. Interferon Cytokine Res. (2005) [Pubmed]
  4. Lack of association between RNASEL Arg462Gln variant and the risk of breast cancer. Sevinç, A., Yannoukakos, D., Konstantopoulou, I., Manguoglu, E., Lüleci, G., Colak, T., Akyerli, C., Colakoglu, G., Tez, M., Sayek, I., Gerassimos, V., Nasioulas, G., Papadopoulou, E., Florentin, L., Kontogianni, E., Bozkurt, B., Kocabas, N.A., Karakaya, A.E., Yulug, I.G., Ozçelik, T. Anticancer Res. (2004) [Pubmed]
  5. RNASEL mutation screening and association study in Ashkenazi and non-Ashkenazi prostate cancer patients. Orr-Urtreger, A., Bar-Shira, A., Bercovich, D., Matarasso, N., Rozovsky, U., Rosner, S., Soloviov, S., Rennert, G., Kadouri, L., Hubert, A., Rennert, H., Matzkin, H. Cancer Epidemiol. Biomarkers Prev. (2006) [Pubmed]
  6. Association of RNASEL variants with prostate cancer risk in Hispanic Caucasians and African Americans. Shook, S.J., Beuten, J., Torkko, K.C., Johnson-Pais, T.L., Troyer, D.A., Thompson, I.M., Leach, R.J. Clin. Cancer Res. (2007) [Pubmed]
  7. A study of the interferon antiviral mechanism: apoptosis activation by the 2-5A system. Castelli, J.C., Hassel, B.A., Wood, K.A., Li, X.L., Amemiya, K., Dalakas, M.C., Torrence, P.F., Youle, R.J. J. Exp. Med. (1997) [Pubmed]
  8. Impact of virus infection on host cell protein synthesis. Schneider, R.J., Shenk, T. Annu. Rev. Biochem. (1987) [Pubmed]
  9. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Carpten, J., Nupponen, N., Isaacs, S., Sood, R., Robbins, C., Xu, J., Faruque, M., Moses, T., Ewing, C., Gillanders, E., Hu, P., Bujnovszky, P., Makalowska, I., Baffoe-Bonnie, A., Faith, D., Smith, J., Stephan, D., Wiley, K., Brownstein, M., Gildea, D., Kelly, B., Jenkins, R., Hostetter, G., Matikainen, M., Schleutker, J., Klinger, K., Connors, T., Xiang, Y., Wang, Z., De Marzo, A., Papadopoulos, N., Kallioniemi, O.P., Burk, R., Meyers, D., Grönberg, H., Meltzer, P., Silverman, R., Bailey-Wilson, J., Walsh, P., Isaacs, W., Trent, J. Nat. Genet. (2002) [Pubmed]
  10. Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action. Zhou, A., Hassel, B.A., Silverman, R.H. Cell (1993) [Pubmed]
  11. Structural and functional features of the 37-kDa 2-5A-dependent RNase L in chronic fatigue syndrome. Shetzline, S.E., Martinand-Mari, C., Reichenbach, N.L., Buletic, Z., Lebleu, B., Pfleiderer, W., Charubala, R., De Meirleir, K., De Becker, P., Peterson, D.L., Herst, C.V., Englebienne, P., Suhadolnik, R.J. J. Interferon Cytokine Res. (2002) [Pubmed]
  12. Inhibition of HIV-1 replication and activation of RNase L by phosphorothioate/phosphodiester 2',5'-oligoadenylate derivatives. Sobol, R.W., Henderson, E.E., Kon, N., Shao, J., Hitzges, P., Mordechai, E., Reichenbach, N.L., Charubala, R., Schirmeister, H., Pfleiderer, W. J. Biol. Chem. (1995) [Pubmed]
  13. Purine 8-bromination modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates. Possible influence of glycosyl torsion angle. Lesiak, K., Torrence, P.F. J. Biol. Chem. (1987) [Pubmed]
  14. Analysis of the RNASEL gene in familial and sporadic prostate cancer. Wang, L., McDonnell, S.K., Elkins, D.A., Slager, S.L., Christensen, E., Marks, A.F., Cunningham, J.M., Peterson, B.J., Jacobsen, S.J., Cerhan, J.R., Blute, M.L., Schaid, D.J., Thibodeau, S.N. Am. J. Hum. Genet. (2002) [Pubmed]
  15. A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews. Rennert, H., Bercovich, D., Hubert, A., Abeliovich, D., Rozovsky, U., Bar-Shira, A., Soloviov, S., Schreiber, L., Matzkin, H., Rennert, G., Kadouri, L., Peretz, T., Yaron, Y., Orr-Urtreger, A. Am. J. Hum. Genet. (2002) [Pubmed]
  16. HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. Malathi, K., Paranjape, J.M., Ganapathi, R., Silverman, R.H. Cancer Res. (2004) [Pubmed]
  17. Implications for RNase L in prostate cancer biology. Silverman, R.H. Biochemistry (2003) [Pubmed]
  18. Mutational analysis of susceptibility genes RNASEL/HPC1, ELAC2/HPC2, and MSR1 in sporadic prostate cancer. Nupponen, N.N., Wallén, M.J., Ponciano, D., Robbins, C.M., Tammela, T.L., Vessella, R.L., Carpten, J.D., Visakorpi, T. Genes Chromosomes Cancer (2004) [Pubmed]
  19. An Alternative Spliced RNASEL Variant in Peripheral Blood Leukocytes. Rennert, H., Sadowl, C., Edwards, J., Bantly, D., Molinaro, R.J., Orr-Urtreger, A., Bagg, A., Moore, J.S., Silverman, R.H. J. Interferon Cytokine Res. (2006) [Pubmed]
  20. Cloning and characterization of a RNAse L inhibitor. A new component of the interferon-regulated 2-5A pathway. Bisbal, C., Martinand, C., Silhol, M., Lebleu, B., Salehzada, T. J. Biol. Chem. (1995) [Pubmed]
  21. The 2-5A/RNase L/RNase L inhibitor (RLI) [correction of (RNI)] pathway regulates mitochondrial mRNAs stability in interferon alpha-treated H9 cells. Le Roy, F., Bisbal, C., Silhol, M., Martinand, C., Lebleu, B., Salehzada, T. J. Biol. Chem. (2001) [Pubmed]
  22. Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates. Xiang, Y., Wang, Z., Murakami, J., Plummer, S., Klein, E.A., Carpten, J.D., Trent, J.M., Isaacs, W.B., Casey, G., Silverman, R.H. Cancer Res. (2003) [Pubmed]
  23. Association of hereditary prostate cancer gene polymorphic variants with sporadic aggressive prostate carcinoma. Noonan-Wheeler, F.C., Wu, W., Roehl, K.A., Klim, A., Haugen, J., Suarez, B.K., Kibel, A.S. Prostate (2006) [Pubmed]
  24. A newly discovered function for RNase L in regulating translation termination. Le Roy, F., Salehzada, T., Bisbal, C., Dougherty, J.P., Peltz, S.W. Nat. Struct. Mol. Biol. (2005) [Pubmed]
  25. Microwave exposure alters the expression of 2-5A-dependent RNase. Krause, D., Mullins, J.M., Penafiel, L.M., Meister, R., Nardone, R.M. Radiat. Res. (1991) [Pubmed]
  26. Functional characterization of 2',5'-linked oligoadenylate binding determinant of human RNase L. Nakanishi, M., Tanaka, N., Mizutani, Y., Mochizuki, M., Ueno, Y., Nakamura, K.T., Kitade, Y. J. Biol. Chem. (2005) [Pubmed]
  27. Blockage of NF-kappa B signaling by selective ablation of an mRNA target by 2-5A antisense chimeras. Maran, A., Maitra, R.K., Kumar, A., Dong, B., Xiao, W., Li, G., Williams, B.R., Torrence, P.F., Silverman, R.H. Science (1994) [Pubmed]
  28. RNase L inhibitor (RLI) antisense constructions block partially the down regulation of the 2-5A/RNase L pathway in encephalomyocarditis-virus-(EMCV)-infected cells. Martinand, C., Salehzada, T., Silhol, M., Lebleu, B., Bisbal, C. Eur. J. Biochem. (1998) [Pubmed]
  29. Interaction between the androgen receptor and RNase L mediates a cross-talk between the interferon and androgen signaling pathways. Bettoun, D.J., Scafonas, A., Rutledge, S.J., Hodor, P., Chen, O., Gambone, C., Vogel, R., McElwee-Witmer, S., Bai, C., Freedman, L., Schmidt, A. J. Biol. Chem. (2005) [Pubmed]
  30. Characterization of RNABP, an RNA binding protein that associates with RNase L. Le Roy, F., Laskowska, A., Silhol, M., Salehzada, T., Bisbal, C. J. Interferon Cytokine Res. (2000) [Pubmed]
  31. Caspase-dependent apoptosis by 2',5'-oligoadenylate activation of RNase L is enhanced by IFN-beta. Rusch, L., Zhou, A., Silverman, R.H. J. Interferon Cytokine Res. (2000) [Pubmed]
  32. Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1. Lange, E.M., Gillanders, E.M., Davis, C.C., Brown, W.M., Campbell, J.K., Jones, M., Gildea, D., Riedesel, E., Albertus, J., Freas-Lutz, D., Markey, C., Giri, V., Dimmer, J.B., Montie, J.E., Trent, J.M., Cooney, K.A. Prostate (2003) [Pubmed]
  33. Single nucleotide polymorphisms in genes for 2'-5'-oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection. Yakub, I., Lillibridge, K.M., Moran, A., Gonzalez, O.Y., Belmont, J., Gibbs, R.A., Tweardy, D.J. J. Infect. Dis. (2005) [Pubmed]
  34. Post-transcriptional regulation of RNase-L expression is mediated by the 3'-untranslated region of its mRNA. Li, X.L., Andersen, J.B., Ezelle, H.J., Wilson, G.M., Hassel, B.A. J. Biol. Chem. (2007) [Pubmed]
  35. Role of genetic polymorphisms of the RNASEL gene on familial prostate cancer risk in a Japanese population. Nakazato, H., Suzuki, K., Matsui, H., Ohtake, N., Nakata, S., Yamanaka, H. Br. J. Cancer (2003) [Pubmed]
  36. Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer severity in European American and African American men. Rennert, H., Zeigler-Johnson, C.M., Addya, K., Finley, M.J., Walker, A.H., Spangler, E., Leonard, D.G., Wein, A., Malkowicz, S.B., Rebbeck, T.R. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
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