title: The human nuclear poly(a)-binding protein promotes RNA hyperadenylation and decay.
abstract: Control of nuclear RNA stability is essential for proper gene expression, but the mechanisms governing RNA degradation in mammalian nuclei are poorly defined. In this study, we uncover a mammalian RNA decay pathway that depends on the nuclear poly(A)-binding protein (PABPN1), the poly(A) polymerases (PAPs), PAPα and PAPγ, and the exosome subunits RRP6 and DIS3. Using a targeted knockdown approach and nuclear RNA reporters, we show that PABPN1 and PAPα, redundantly with PAPγ, generate hyperadenylated decay substrates that are recognized by the exosome and degraded. Poly(A) tail extension appears to be necessary for decay, as cordycepin treatment or point mutations in the PAP-stimulating domain of PABPN1 leads to the accumulation of stable transcripts with shorter poly(A) tails than controls. Mechanistically, these data suggest that PABPN1-dependent promotion of PAP activity can stimulate nuclear RNA decay. Importantly, efficiently exported RNAs are unaffected by this decay pathway, supporting an mRNA quality control function for this pathway. Finally, analyses of both bulk poly(A) tails and specific endogenous transcripts reveals that a subset of nuclear RNAs are hyperadenylated in a PABPN1-dependent fashion, and this hyperadenylation can be either uncoupled or coupled with decay. Our results highlight a complex relationship between PABPN1, PAPα/γ, and nuclear RNA decay, and we suggest that these activities may play broader roles in the regulation of human gene expression.
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Bresson
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Conrad
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics; D005095:Exoribonucleases / Q000378:metabolism; D063326:Exosome Multienzyme Ribonuclease Complex / Q000378:metabolism; D055354:Exosomes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039122:Poly(A)-Binding Protein I / Q000235:genetics* / Q000378:metabolism; D026723:Polyadenylation / Q000235:genetics*; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D039122:Poly(A)-Binding Protein I; D012333:RNA, Messenger; D005095:Exoribonucleases; D063326:Exosome Multienzyme Ribonuclease Complex; C551543:DIS3 protein, human; C077044:EXOSC10 protein, human