title: Depletion of NEAT1 lncRNA attenuates nucleolar stress by releasing sequestered P54nrb and PSF to facilitate c-Myc translation.
abstract: Altered expression of NEAT1, the architectural long non-coding RNA (lncRNA) of nuclear paraspeckles, has been reported during tumorigenesis, as well as under various cellular stress conditions. Here we report that the depletion of NEAT1 lncRNA alleviates nucleolar stress during RNAP I inhibition through releasing sequestered P54nrb and PSF to facilitate the IRES-dependent translation of c-Myc. RNAP I inhibitor CX5461 disrupts the SL1-rDNA interaction and induces nucleolar disruption, demonstrated by the accumulation of fibrillarin-containing nucleoplasmic foci and nucleolar clearance of ribosomal proteins in HeLa cells. Antisense oligonucleotide-mediated depletion of NEAT1 lncRNA significantly attenuated the RNAP I inhibition and its related nucleolar disruption. Interestingly, induction in the levels of c-Myc protein was observed in NEAT1-depeleted cells under RNAP I inhibition. NEAT1-associated paraspeckle proteins P54nrb and PSF have been reported as positive regulators of c-Myc translation through interaction with c-Myc IRES. Indeed, an increased association of P54nrb and PSF with c-Myc mRNA was observed in NEAT1-depleted cells. Moreover, apoptosis was observed in HeLa cells depleted of P54nrb and PSF, further confirming the positive involvement of P54nrb and PSF in cell proliferation. Together, our results suggest that NEAT1 depletion rescues CX5461-induced nucleolar stress through facilitating c-Myc translation by relocating P54nrb/PSF from nuclear paraspeckles to c-Myc mRNAs.
authors.affiliation: Department of Core Antisense Research, IONIS Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA, United States of America.
authors.forename: Wen
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Core Antisense Research, IONIS Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA, United States of America.
authors.forename: Xue-Hai
authors.initials: XH
authors.lastname: Liang
authors.affiliation: Department of Core Antisense Research, IONIS Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Core Antisense Research, IONIS Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA, United States of America.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: De Hoyos
authors.affiliation: Department of Core Antisense Research, IONIS Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA, United States of America.
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Crooke
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D016259:Genes, myc; D006801:Humans; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism*; D050810:Octamer Transcription Factors / Q000378:metabolism*; D000072670:PTB-Associated Splicing Factor / Q000378:metabolism*; D014176:Protein Biosynthesis; D062085:RNA, Long Noncoding / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C577276:NEAT1 long non-coding RNA, human; C083214:NONO protein, human; D034521:Nuclear Matrix-Associated Proteins; D050810:Octamer Transcription Factors; D000072670:PTB-Associated Splicing Factor; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins