Regulated poly(A) tail shortening in somatic cells mediated by cap-proximal translational repressor proteins and ribosome association.
The poly(A) tail plays an important role in translation initiation. We report the identification of a mechanism that operates in mammalian somatic cells, and couples mRNA poly(A) tail length with its translation state. The regulation of human ferritin L-chain mRNA by iron-responsive elements (IREs) and iron regulatory proteins (IRPs) is subject to this mechanism: translational repression imposed by IRP binding to the IRE of ferritin L-chain mRNA induces poly(A) tail shortening. For the accumulation of mRNAs with short poly(A) tails, IRP binding to an IRE per se is not sufficient, but must cause translational repression. Interestingly, puromycin and verrucarin (general translation inhibitors that dissociate mRNAs from ribosomes) mimick the negative effect of the specific translational repressor proteins on poly(A) tail length, whereas cycloheximide and anisomycin (general translation inhibitors that maintain the association between mRNAs and ribosomes) preserve long poly(A) tails. Thus, the ribosome association of the mRNA appears to represent the critical determinant. These findings identify a novel mechanism of regulated polyadenylation as a consequence of translational control. They reveal differences in poly(A) tail metabolism between polysomal and mRNP-associated mRNAs. A possible role of this mechanism in the maintenance of translational repression is discussed.
Muckenthaler
M
M
Gene Expression Programme, European Molecular Biology Laboratory, Heidelberg, Germany.
Gunkel
N
N
Stripecke
R
R
Hentze
M W
MW
D000818:Animals; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D019382:Human Growth Hormone / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D007700:Kinetics; D008322:Mammals; D011061:Poly A / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D012315:RNA Caps; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000235:genetics* / Q000378:metabolism
D012315:RNA Caps; D011994:Recombinant Proteins; D012097:Repressor Proteins; D019382:Human Growth Hormone; D011061:Poly A; D005293:Ferritins; D007501:Iron