Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast

eLife

Rachael Emily Turner¹  Angavai Swaminathan¹  Calvin A Kraupner-Taylor¹  Traude H Beilharz¹  Belinda J Goldie¹  Paul F Harrison²  Michael See²  Darren J Creek³  Amanda L Peterson³  David R Powell⁴  Ralf B Schittenhelm⁵  Bernhard Dichtl⁶ 

[1] Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia;Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia;Monash Bioinformatics Platform, Monash University, Melbourne, Australia;Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia;Monash Bioinformatics Platform, Monash University, Melbourne, Australia;Monash Proteomics & Metabolomics Facility, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia;School of Life and Environmental Sciences, Deakin University, Geelong, Australia;

关键词: alternative polyadenylation;    transcription elongation;    cleavage;    polyadenylation;    cordycepin;    mycophenolic acid;    Sen1;    S. cerevisiae;   

DOI  :  10.7554/eLife.65331

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Most eukaryotic mRNAs accommodate alternative sites of poly(A) addition in the 3’ untranslated region in order to regulate mRNA function. Here, we present a systematic analysis of 3’ end formation factors, which revealed 3’UTR lengthening in response to a loss of the core machinery, whereas a loss of the Sen1 helicase resulted in shorter 3’UTRs. We show that the anti-cancer drug cordycepin, 3’ deoxyadenosine, caused nucleotide accumulation and the usage of distal poly(A) sites. Mycophenolic acid, a drug which reduces GTP levels and impairs RNA polymerase II (RNAP II) transcription elongation, promoted the usage of proximal sites and reversed the effects of cordycepin on alternative polyadenylation. Moreover, cordycepin-mediated usage of distal sites was associated with a permissive chromatin template and was suppressed in the presence of an rpb1 mutation, which slows RNAP II elongation rate. We propose that alternative polyadenylation is governed by temporal coordination of RNAP II transcription and 3’ end processing and controlled by the availability of 3’ end factors, nucleotide levels and chromatin landscape.

【 授权许可】

CC BY