Distinct regulation of alternative polyadenylation and gene expression by nuclear poly(A) polymerases.
Nucleic Acids Res
; 45(15): 8930-8942, 2017 Sep 06.
Article
em En
| MEDLINE
| ID: mdl-28911096
ABSTRACT
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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Base de dados:
MEDLINE
Assunto principal:
Polinucleotídeo Adenililtransferase
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Regulação da Expressão Gênica
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Fator de Iniciação 4A em Eucariotos
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PTEN Fosfo-Hidrolase
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RNA Longo não Codificante
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article