TY - JOUR
T1 - Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast
AU - Turner, Rachael Emily
AU - Harrison, Paul F.
AU - Swaminathan, Angavai
AU - Kraupner-Taylor, Calvin A.
AU - Goldie, Belinda J.
AU - See, Michael
AU - Peterson, Amanda L.
AU - Schittenhelm, Ralf B.
AU - Powell, David R.
AU - Creek, Darren J.
AU - Dichtl, Bernhard
AU - Beilharz, Traude H.
N1 - Funding Information:
We thank the following researchers for strain and plasmid resources: David Brow, Michael Culbertson, Walter Keller, Lionel Minvielle-Sebastia, Beate Schwer, Mike Stark, Maurice Swanson, Franc¸ oise Wyers, Craig Kaplan and Wendy Olivas. Melissa J Curtis is acknowledged for her technical assistance in the experimental data collection early in the project, and members of the Beilharz laboratory provided critical feedback. The MHTP Medical Genomics Facility, the Monash Proteomics and Metabo-lomics Facility, Micromon, and the Monash Bioinformatics Platform are thanked for the provision of technical support and infrastructure. Monash research technology platforms are enabled by Bioplat-forms Australia (BPA) and the National Collaborative Research Infrastructure Strategy (NCRIS). RET was supported by an Australian Postgraduate Research award. THB was supported by a Monash Bio Discovery Fellowship and grants from the Australian Research Council (ARC: DP170100569 and FT180100049).
Funding Information:
We thank the following researchers for strain and plasmid resources: David Brow, Michael Culbert-son, Walter Keller, Lionel Minvielle-Sebastia, Beate Schwer, Mike Stark, Maurice Swanson, Fran?oise Wyers, Craig Kaplan and Wendy Olivas. Melissa J Curtis is acknowledged for her technical assistance in the experimental data collection early in the project, and members of the Beilharz laboratory provided critical feedback. The MHTP Medical Genomics Facility, the Monash Proteomics and Metabolomics Facility, Micromon, and the Monash Bioinformatics Platform are thanked for the provision of technical support and infrastructure. Monash research technology platforms are enabled by Bioplat-forms Australia (BPA) and the National Collaborative Research Infrastructure Strategy (NCRIS). RET was supported by an Australian Postgraduate Research award. THB was supported by a Monash Bio Discovery Fellowship and grants from the Australian Research Council (ARC: DP170100569 and FT180100049).
Publisher Copyright:
© Turner et al.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85110941473
U2 - 10.7554/eLife.65331
DO - 10.7554/eLife.65331
M3 - Article
C2 - 34232857
AN - SCOPUS:85110941473
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e65331
ER -
SDG 3 Good Health and Well-being