Thursday, September 7, 2006

mRNA quality control

drj writes "Messenger RNA (mRNA) with a premature termination codon (PTC) undergoes nonsense mediated decay (NMD). NMD is thought to protect against amino-terminal protein fragments that could be disruptive, for example, by acting as dominant negative mutants. Muscular dystrophy, Marfan syndrome, and other human diseases are caused by premature termination. Hillman and colleagues earlier determined that over one-third of alternatively-spliced human mRNAs have a PTC. Since NMD mechanisms were only recently discovered, they suspected many mRNAs in the databases might contain previously unrecognized PTCs and would have undergone NMD in vivo. Here, they aligned protein sequences from SWISS-PROT with gene sequences from Genbank to identify ~8% of entries that contain a PTC. Important biological effects could be attributed to NMD. For example, an intronic polymorphism linked to type II diabetes reduces 4 of 8 calpain-10 mRNA isoforms. These same 4 isoforms contain a PTC, suggesting NMD underlies reduced expression, causing disease. Similar analysis of CDC-like kinases and a receptor containing a death domain suggests previously unsuspected roles for NMD.
PubMed Hillman et al. Genome Biology 5:R8. January 2, 2004
Background: In mammals, "premature" is a stop codon >50 nucleotides upstream of the last intron. mRNAs with PTC are flagged for degradation by the persistent splice junction protein complexes, which are normally cleared by the ribosome.
An unappreciated role for RNA surveillance R Tyler Hillman, Richard E Green and Steven E Brenner. Genome Biology 2004, 5:R8. online at genomebiology"

No comments: