The rules and impact of nonsense-mediated mRNA decay in human cancers.
Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance pathway termed nonsense-mediated mRNA decay (NMD). However, the efficiency of NMD varies; it is inefficient when a PTC is located downstream of the last exon junction complex (EJC). We used matched exome and transcriptome data from 9,769 human tumors to systematically elucidate the rules of NMD targeting in human cells. An integrated model incorporating multiple rules beyond the canonical EJC model explains approximately three-fourths of the non-random variance in NMD efficiency across thousands of PTCs. We also show that dosage compensation may sometimes mask the effects of NMD. Applying the NMD model identifies signatures of both positive and negative selection on NMD-triggering mutations in human tumors and provides a classification for tumor-suppressor genes.
EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Rik G H
RG
Lindeboom
EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Division of Electronics, Rudjer Boskovic Institute, Zagreb, Croatia.
Fran
0000-0002-7811-6711
F
Supek
EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Ben
B
Lehner
D000818:Animals; D018389:Codon, Nonsense; D018388:Codon, Terminator; D004330:Drosophila; D005091:Exons; D016147:Genes, Tumor Suppressor; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D059365:Nonsense Mediated mRNA Decay; D014176:Protein Biosynthesis
D018389:Codon, Nonsense; D018388:Codon, Terminator