Defects in mTR stability and telomerase activity produced by the Dkc1 A353V mutation in dyskeratosis congenita are rescued by a peptide from the dyskerin TruB domain
详细信息 查看全文
- 作者：Rosario Machado-Pinilla (1) (2)
Jaime Carrillo (1) (2)
Cristina Manguan-Garcia (1) (2)
Leandro Sastre (1) (2)
Alexander Mentzer (3)
B.-W. Gu (3)
Philip J. Mason (3)
Rosario Perona (1) (2) - 关键词：Dyskeratosis congenita ; Dyskerin ; TERT ; GSE24.2
- 刊名：Clinical and Translational Oncology
- 出版年：2012
- 出版时间：October 2012
- 年：2012
- 卷：14
- 期：10
- 页码：755-763
- 全文大小：605KB
- 参考文献：1. Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42:301鈥?34 CrossRef
2. Osterhage JL, Friedman KL (2009) Chromosome end maintenance by telomerase. J Biol Chem 284:16061鈥?6065 CrossRef
3. Cohen SB, Graham ME, Lovrecz GO et al (2007) Protein composition of catalytically active human telomerase from immortal cells. Science 315:1850鈥?853 CrossRef
4. Meier UT, Blobel G (1994) NAP57, a mammalian nucleolar protein with a putative homolog in yeast and bacteria. J Cell Biol 127:1505鈥?514 CrossRef
5. Decatur WA, Fournier MJ (2002) rRNA modifications and ribosome function. Trends Biochem Sci 27:344鈥?51 CrossRef
6. Ni J, Tien AL, Fournier MJ (1997) Small nucleolar RNAs direct site-specific synthesis of pseudouridine in ribosomal RNA. Cell 89:565鈥?73 CrossRef
7. Yang Y, Isaac C, Wang C et al (2000) Conserved composition of mammalian box H/ACA and box C/D small nucleolar ribonucleoprotein particles and their interaction with the common factor Nopp 140. Mol Biol Cell 11:567鈥?77
8. Heiss NS, Knight SW, Vulliamy TJ et al (1998) X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 19:32鈥?8 CrossRef
9. Kirwan M, Dokal I (2008) Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet 73:103鈥?12 CrossRef
10. Machado-Pinilla R, Sanchez-Perez I, Murguia JR, Sastre L, Perona R (2008) A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells. Blood 111:2606鈥?614 CrossRef
11. Knight SW, Heiss NS, Vulliamy TJ et al (1999) X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. Am J Hum Genet 65:50鈥?8 CrossRef
12. Vulliamy TJ, Marrone A, Knight SW et al (2006) Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 107:2680鈥?685 CrossRef
13. Mochizuki Y, He J, Kulkarni S, Bessler M, Mason PJ (2004) Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing. Proc Natl Acad Sci USA 101:10756鈥?0761 CrossRef
14. Oh S, Song YH, Kim UJ, Yim J, Kim TK (1999) In vivo and in vitro analyses of Myc for differential promoter activities of the human telomerase (hTERT) gene in normal and tumor cells. Biochem Biophys Res Commun 263:361鈥?65 CrossRef
15. Zhao JQ, Hoare SF, McFarlane R et al (1998) Cloning and characterization of human and mouse telomerase RNA gene promoter sequences. Oncogene 16:1345鈥?350 CrossRef
16. Kalinin A, Thoma NH, Iakovenko A et al (2001) Expression of mammalian geranylgeranyltransferase type-II in / Escherichia coli and its application for in vitro prenylation of Rab proteins. Protein Expr Purif 22:84鈥?1 CrossRef
17. Wright WE, Shay JW, Piatyszek MA (1995) Modifications of a telomeric repeat amplification protocol (TRAP) result in increased reliability, linearity and sensitivity. Nucleic Acids Res 23:3794鈥?795 CrossRef
18. Sanchez-Perez I, Murguia JR, Perona R (1998) Cisplatin induces a persistent activation of JNK that is related to cell death. Oncogene 16:533鈥?40 CrossRef
19. Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402:551鈥?55 CrossRef
20. Ramamurthy V, Swann SL, Paulson JL, Spedaliere CJ, Mueller EG (1999) Critical aspartic acid residues in pseudouridine synthases. J Biol Chem 274:22225鈥?2230 CrossRef
21. Spedaliere CJ, Hamilton CS, Mueller EG (2000) Functional importance of motif I of pseudouridine synthases: mutagenesis of aligned lysine and proline residues. Biochemistry 39:9459鈥?465 CrossRef
22. Zucchini C, Strippoli P, Biolchi A et al (2003) The human TruB family of pseudouridine synthase genes, including the Dyskeratosis Congenita 1 gene and the novel member TRUB1. Int J Mol Med 11:697鈥?04
23. Wong JM, Collins K (2006) Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita. Genes Dev 20:2848鈥?858 CrossRef
24. Dokal I (2000) Dyskeratosis congenita in all its forms. Br J Haematol 110:768鈥?79 CrossRef
25. de la Fuente J, Dokal I (2007) Dyskeratosis congenita: advances in the understanding of the telomerase defect and the role of stem cell transplantation. Pediatr Transplant 11:584鈥?94 CrossRef
26. Marrone A, Mason PJ (2003) Dyskeratosis congenita. Cell Mol Life Sci 60:507鈥?17 CrossRef
27. Zeng XL, Thumati NR, Fleisig HB et al (2011) The accumulation and not the specific activity of telomerase ribonucleoprotein determines telomere maintenance deficiency in X-linked dyskeratosis congenita. Hum Mol Genet (epub ahead of print Nov 16) - 作者单位：Rosario Machado-Pinilla (1) (2)
Jaime Carrillo (1) (2)
Cristina Manguan-Garcia (1) (2)
Leandro Sastre (1) (2)
Alexander Mentzer (3)
B.-W. Gu (3)
Philip J. Mason (3)
Rosario Perona (1) (2)
1. Instituto de Investigaciones Biom茅dicas CSIC/UAM, IDIPaz (Biomarkers and Experimental Therapeutics), C/Arturo Duperier, 4, 28029, Madrid, Spain
2. CIBER de Enfermedades Raras, Valencia, Spain
3. Leonard and Madlyn Abramson Pediatric Research Center, The Childrens Hospital of Philadelphia, 4th and Civic Center Boulevard Philadelphia, Philadelphia, PA, 19104-4318, USA
文摘
Background The predominant X-linked form of dyskeratosis congenita results from mutations in dyskerin, a protein required for ribosomal RNA modification that is also a component of the telomerase complex. We have previously found that expression of an internal fragment of dyskerin (GSE24.2) rescues telomerase activity in X-linked dyskeratosis congenita (X-DC) patient cells. Materials and Methods Here, we have generated F9 mouse cell lines expressing the most frequent mutation found in X-DC patients, A353V and study the effect of expressing the GSE24.2 cDNA or GSE24.2 peptide on telomerase activity by TRAP assay, and mTERT and mTR expression by Q-PCR. Point mutation in GSE24.2 residues were generated by site-directed mutagenesis. Results Expression of GSE24.2 increases mTR and to a lesser extent mTERT RNA levels, and leads to recovery of telomerase activity. Point mutations in GSE24.2 residues known to be highly conserved and crucial for the pseudouridine-synthase activity of dyskerin abolished the effect of the peptide. Recovery of telomerase activity and increase in mTERT levels were found when the GSE24.2 peptide purified from bacteria was introduced into the cells. Moreover, mTR stability was also rescued by transfection of the peptide GSE24.2. Discussion These data indicate that supplying GSE24.2, either from a cDNA vector, or as a peptide, can reduces the pathogenic effects of Dkc1 mutations and could form the basis of a novel therapeutic approach.