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Human Molecular Genetics Advance Access published online on July 6, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi245
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received May 10, 2005
Revised June 23, 2005
Accepted July 1, 2005

Article

DIFFERENTIAL NONSENSE MEDIATED DECAY OF MUTATED mRNAs IN MISMATCH REPAIR DEFICIENT COLORECTAL CANCERS

Jamila El Bchiri 1, Olivier Buhard 1, Virginie Penard-Lacronique 2, Gilles Thomas 1, Richard Hamelin 1, and Alex Duval 1*

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

* To whom correspondence should be addressed.
Alex Duval, E-mail: alex.duval{at}cephb.fr


  Abstract

The Nonsense Mediated Decay (NMD) system normally targets mRNAs with premature termination codons (PTC) for rapid degradation. We investigated for a putative role of NMD in cancers with microsatellite instability (MSI-H cancers), since 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 to 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) while 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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