Human Molecular Genetics, 2002, Vol. 11, No. 23 2805-2814
© 2002 Oxford University Press
The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons
1Laboratoire de Génétique UMR 5641, Faculté de Médecine Rockefeller, 69373 Lyon cedex 08, France, 2International Agency for Research on Cancer, 69372 Lyon cedex 03, France, 3Laboratoire de Génétique, Hôpital Edouard Herriot, 69437 Lyon cedex 03, France and 4Service de Génétique Oncologique, Institut Curie, 75248 Paris cedex 05, France
Received March 28, 2002; Accepted September 10, 2002
Germline mutations in the BRCA1 gene are scattered over the 22 coding exons and most of them generate premature termination codons (PTCs). A mechanism called nonsense-mediated mRNA decay (NMD) is known to specifically degrade transcripts with PTCs; however, steady-state amounts of mutant BRCA1 mRNAs have very rarely been measured. Although growing evidence implicates downstream exon–exon junctions (EEJs) as critical determinants for discrimination between normal stop codons and PTCs, requirements concerning the minimal and maximal distance between PTCs and downstream EEJs are still debated. We assessed the relative amount of transcripts encoded by BRCA1 alleles harbouring 30 different truncating mutations in lymphoblastoid cell lines established from carriers from breast/ovarian cancer families. We found that NMD is triggered by 80% of PTC+ alleles and results in a 1.5- to 5-fold reduction in mRNA abundance. All truncating mutations located in the 3.4 kb long central exon are subject to NMD, irrespective of their distance to the downstream EEJ (305 to 3395 nt). PTCs not leading to NMD are either located in the last exon or very close to the translation initiation codon. We hypothesize that reinitiation could explain why transcripts carrying early PTCs escape NMD. This is the first study challenging the NMD rules, which have been established through the study of minigenes, by analysing a large series of mutant endogenous alleles.
* To whom correspondence should be addressed. Tel: +33 478777587; Fax: +33 478777220; Email: smazoyer{at}rockefeller.univ-lyon1.fr
Present address: Institut Gustave Roussy, Villejuif, France.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Rinne, S. E. Clements, E. Lamme, P. H.G. Duijf, E. Bolat, R. Meijer, H. Scheffer, E. Rosser, T. Y. Tan, J. A. McGrath, et al. A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes Hum. Mol. Genet., July 1, 2008; 17(13): 1968 - 1977. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Gardner Hypoxic Inhibition of Nonsense-Mediated RNA Decay Regulates Gene Expression and the Integrated Stress Response Mol. Cell. Biol., June 1, 2008; 28(11): 3729 - 3741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Milne, A. Osorio, T. R. y Cajal, A. Vega, G. Llort, M. de la Hoya, O. Diez, M. C. Alonso, C. Lazaro, I. Blanco, et al. The Average Cumulative Risks of Breast and Ovarian Cancer for Carriers of Mutations in BRCA1 and BRCA2 Attending Genetic Counseling Units in Spain Clin. Cancer Res., May 1, 2008; 14(9): 2861 - 2869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Duboscq-Bidot, P. Xu, P. Charron, N. Neyroud, G. Dilanian, A. Millaire, V. Bors, M. Komajda, and E. Villard Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy Cardiovasc Res, January 1, 2008; 77(1): 118 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ghosh, Y. Lu, A. Katz, Y. Hu, and R. Li Tumor suppressor BRCA1 inhibits a breast cancer-associated promoter of the aromatase gene (CYP19) in human adipose stromal cells Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E246 - E252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Disset, C.F. Bourgeois, N. Benmalek, M. Claustres, J. Stevenin, and S. Tuffery-Giraud An exon skipping-associated nonsense mutation in the dystrophin gene uncovers a complex interplay between multiple antagonistic splicing elements Hum. Mol. Genet., March 15, 2006; 15(6): 999 - 1013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Stockklausner, S. Breit, G. Neu-Yilik, N. Echner, M. W. Hentze, A. E. Kulozik, and N. H. Gehring The uORF-containing thrombopoietin mRNA escapes nonsense-mediated decay (NMD). Nucleic Acids Res., January 1, 2006; 34(8): 2355 - 2363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P K Lovelock, S Healey, W Au, E Y M Sum, A Tesoriero, E M Wong, S Hinson, R Brinkworth, A Bekessy, O Diez, et al. Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants J. Med. Genet., January 1, 2006; 43(1): 74 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yamanegi, S. Tang, and Z.-M. Zheng Kaposi's Sarcoma-Associated Herpesvirus K8{beta} Is Derived from a Spliced Intermediate of K8 Pre-mRNA and Antagonizes K8{alpha} (K-bZIP) To Induce p21 and p53 and Blocks K8{alpha}-CDK2 Interaction J. Virol., November 15, 2005; 79(22): 14207 - 14221. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Kis, J. A. Snipes, and D. W. Busija Acetaminophen and the Cyclooxygenase-3 Puzzle: Sorting out Facts, Fictions, and Uncertainties J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 1 - 7. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pavlicek, V. N. Noskov, N. Kouprina, J. C. Barrett, J. Jurka, and V. Larionov Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition Hum. Mol. Genet., November 15, 2004; 13(22): 2737 - 2751. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Inacio, A. L. Silva, J. Pinto, X. Ji, A. Morgado, F. Almeida, P. Faustino, J. Lavinha, S. A. Liebhaber, and L. Romao Nonsense Mutations in Close Proximity to the Initiation Codon Fail to Trigger Full Nonsense-mediated mRNA Decay J. Biol. Chem., July 30, 2004; 279(31): 32170 - 32180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. W. Harries, A. T. Hattersley, and S. Ellard Messenger RNA Transcripts of the Hepatocyte Nuclear Factor-1{alpha} Gene Containing Premature Termination Codons Are Subject to Nonsense-Mediated Decay Diabetes, February 1, 2004; 53(2): 500 - 504. [Abstract] [Full Text]
|
|
|
|
|
|
P. Hohenstein and R. Fodde Of mice and (wo)men: genotype-phenotype correlations in BRCA1 Hum. Mol. Genet., October 15, 2003; 12(90002): R271 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jakubowska, S. A. Narod, D. E. Goldgar, M. Mierzejewski, B. Masojc, K. Nej, J. Huzarska, T. Byrski, B. Gorski, and J. Lubinski Breast Cancer Risk Reduction Associated with the RAD51 Polymorphism among Carriers of the BRCA1 5382insC Mutation in Poland Cancer Epidemiol. Biomarkers Prev., May 1, 2003; 12(5): 457 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Montagna, M. D. Palma, C. Menin, S. Agata, A. De Nicolo, L. Chieco-Bianchi, and E. D'Andrea Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families Hum. Mol. Genet., May 1, 2003; 12(9): 1055 - 1061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lynch and A. Kewalramani Messenger RNA Surveillance and the Evolutionary Proliferation of Introns Mol. Biol. Evol., April 1, 2003; 20(4): 563 - 571. [Abstract] [Full Text] [PDF]
|
|