Regulating the rate of mRNA degradation

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Science Signaling  04 Oct 2016:
Vol. 9, Issue 448, pp. ec231
DOI: 10.1126/scisignal.aal0209

Protein acetylation plays multiple roles in gene expression through modification of histones and transcription factors. Sharma et al. showed that the closely related histone acetyltransferases CBP and p300, as well as the histone deacetylases HDAC1 and HDAC2, can also influence gene expression through their effects on the deadenylation of poly(A)-modified messenger RNA [poly(A) mRNA] and thus on mRNA turnover. In an mRNA degradation assay using HeLa cells transfected with a globin mRNA reporter, inhibiting HDAC with trichostatin A (TSA) resulted in faster mRNA degradation. RNA sequencing of whole HeLa cell extracts showed that the half-lives of more than 7000 RNAs were reduced by TSA treatment but that the degradation of mRNAs for replication-dependent histone genes, which lack a poly(A) tail, was unaffected. TSA-induced poly(A) mRNA degradation was reduced in cell lines with siRNA knockdown of NOT1, a scaffolding component of the CCR4-CAF1-NOT enzyme complex that nonselectively deadenylates mRNA. CAF1a was specifically acetylated in HeLa cells by CBP and p300, as determined both in HeLa cells expressing tagged CAF1a and in vitro with purified recombinant proteins. Pharmacological inhibition of CBP decreased the rate of poly(A) mRNA degradation in both HeLa and Drosophila melanogaster S2 cells. Furthermore, HDAC1 or knockdown or overexpression in HEK293T cells supported its involvement in CAF1a deacetylation. Mutating the acetylated lysine residues in CAF1a to glutamine resulted in increased mRNA stability in the presence of TSA. Thus, acetylation appears to function as a mechanism to globally control mRNA turnover rates, which the authors suggest may be particularly important during cellular differentiation.

S. Sharma, F. Poetz, M. Bruer, T. B. N. Ly-Hartig, J. Schott, B. Séraphin, G. Stoecklin, Acetylation-dependent control of global poly(A) RNA degradation by CBP/p300 and HDAC1/2. Mol. Cell 63, 927–938 (2016). [PubMed]

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