Distinct regulation of alternative polyadenylation and gene expression by nuclear poly(A) polymerases

Weimin Li; Wencheng Li; Rakesh S Laishram; Mainul Hoque; Zhe Ji; Bin Tian; Richard A Anderson

doi:10.1093/nar/gkx560

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Distinct regulation of alternative polyadenylation and gene expression by nuclear poly(A) polymerases

Journal article

Open access

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Distinct regulation of alternative polyadenylation and gene expression by nuclear poly(A) polymerases

Weimin Li, Wencheng Li, Rakesh S Laishram, Mainul Hoque, Zhe Ji, Bin Tian and Richard A Anderson

Nucleic acids research, Vol.45(15), pp.8930-8942

09/06/2017

DOI: https://doi.org/10.1093/nar/gkx560

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https://hdl.handle.net/2376/110073

PMCID: PMC5587728

PMID: 28911096

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Abstract

Polynucleotide Adenylyltransferase - metabolism

RNA, Small Interfering - genetics

Humans

Gene Expression Profiling

RNA, Messenger - metabolism

Polynucleotide Adenylyltransferase - genetics

Cell Nucleus - metabolism

Isoenzymes - metabolism

HEK293 Cells

Eukaryotic Initiation Factor-4A - genetics

PTEN Phosphohydrolase - genetics

Signal Transduction

Isoenzymes - genetics

RNA, Messenger - genetics

Gene Expression Regulation

PTEN Phosphohydrolase - metabolism

RNA, Long Noncoding - genetics

Cell Nucleus - genetics

Polyadenylation

Kinetics

Eukaryotic Initiation Factor-4A - metabolism

RNA, Long Noncoding - metabolism

Isoenzymes - antagonists & inhibitors

Polynucleotide Adenylyltransferase - antagonists & inhibitors

RNA, Small Interfering - metabolism

Polyadenylation of nascent RNA by poly(A) polymerase (PAP) is important for 3' end maturation of almost all eukaryotic mRNAs. Most mammalian genes harbor multiple polyadenylation sites (PASs), leading to expression of alternative polyadenylation (APA) isoforms with distinct functions. How poly(A) polymerases may regulate PAS usage and hence gene expression is poorly understood. Here, we show that the nuclear canonical (PAPα and PAPγ) and non-canonical (Star-PAP) PAPs play diverse roles in PAS selection and gene expression. Deficiencies in the PAPs resulted in perturbations of gene expression, with Star-PAP impacting lowly expressed mRNAs and long-noncoding RNAs to the greatest extent. Importantly, different PASs of a gene are distinctly regulated by different PAPs, leading to widespread relative expression changes of APA isoforms. The location and surrounding sequence motifs of a PAS appear to differentiate its regulation by the PAPs. We show Star-PAP-specific PAS usage regulates the expression of the eukaryotic translation initiation factor EIF4A1, the tumor suppressor gene PTEN and the long non-coding RNA NEAT1. The Star-PAP-mediated APA of PTEN is essential for DNA damage-induced increase of PTEN protein levels. Together, our results reveal a PAS-guided and PAP-mediated paradigm for gene expression in response to cellular signaling cues.

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Title: Distinct regulation of alternative polyadenylation and gene expression by nuclear poly(A) polymerases
Creators: Weimin Li - Washington State University, Elson S. Floyd College of Medicine, Department of Biomedical Sciences, Spokane, WA 99202, USA
Wencheng Li - Rutgers New Jersey Medical School, Department of Microbiology, Biochemistry and Molecular Genetics, Newark, NJ 07103, USA
Rakesh S Laishram - University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA
Mainul Hoque - Rutgers New Jersey Medical School, Department of Microbiology, Biochemistry and Molecular Genetics, Newark, NJ 07103, USA
Zhe Ji - Rutgers New Jersey Medical School, Department of Microbiology, Biochemistry and Molecular Genetics, Newark, NJ 07103, USA
Bin Tian - Rutgers New Jersey Medical School, Department of Microbiology, Biochemistry and Molecular Genetics, Newark, NJ 07103, USA
Richard A Anderson - University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA
Publication Details: Nucleic acids research, Vol.45(15), pp.8930-8942
Academic Unit: Biomedical Sciences, Department of
Publisher: England
Grant note: R35 GM134955 / NIGMS NIH HHS R01 GM114386 / NIGMS NIH HHS R01 GM051968 / NIGMS NIH HHS R01 GM084089 / NIGMS NIH HHS
Identifiers: 99900547272301842
Language: English
Resource Type: Journal article