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Human Molecular Genetics Advance Access originally published online on July 6, 2005
Human Molecular Genetics 2005 14(16):2435-2442; doi:10.1093/hmg/ddi245
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Differential nonsense mediated decay of mutated mRNAs in mismatch repair deficient colorectal cancers

Jamila El-Bchiri1, Olivier Buhard1, Virginie Penard-Lacronique2, Gilles Thomas1, Richard Hamelin1 and Alex Duval1,*

1INSERM U434, 27 rue Juliette Dodu, Hôpital Saint-Louis, 75010 Paris, France and 2INSERM EMI 0210, 149 rue de Sèvres, Hôpital Necker, 75015 Paris, France

* To whom correspondence should be addressed. Tel: +33 153725120; Fax: +33 153725192; Email: alex.duval{at}cephb.fr

Received May 10, 2005; Revised June 23, 2005; Accepted July 1, 2005

The nonsense-mediated decay (NMD) system normally targets mRNAs with premature termination codons (PTCs) for rapid degradation. We investigated for a putative role of NMD in cancers with microsatellite instability (MSI-H cancers), because numerous mutant mRNAs containing PTC are generated in these tumors as a consequence of their mismatch repair deficiency. Using a quantitative RT–PCR approach in a large series of colorectal cancer cell lines, we demonstrate a significantly increased rate of degradation of mutant mRNAs containing a PTC compared with wild-type. A specific siRNA strategy was used to inhibit RENT-1 and/or RENT-2 activity, two major genes in the NMD system. This allowed us to show that increased degradation of PTC-containing mRNAs in MSI-H tumors was partly dependent upon NMD activity. The efficiency of NMD for the degradation of mutant mRNAs from target genes was highly variable in these cancers. NMD degraded some of them (TGFßRII, MSH3, GRK4), although allowing the persistent expression of others (BAX, TCF-4). This is of particular interest within the context of a proposed conservation of biological activity for the corresponding mutated proteins. We thus propose that NMD might play an important role in the selection of target gene mutations with a functional role in MSI-H carcinogenesis.


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[Abstract] [Full Text] [PDF]


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