Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate.
The majority of the eukaryotic genome is transcribed, generating a significant number of long intergenic noncoding RNAs (lincRNAs). Although lincRNAs represent the most poorly understood product of transcription, recent work has shown lincRNAs fulfill important cellular functions. In addition to low sequence conservation, poor understanding of structural mechanisms driving lincRNA biology hinders systematic prediction of their function. Here we report the molecular requirements for the recognition of steroid receptors (SRs) by the lincRNA growth arrest-specific 5 (Gas5), which regulates steroid-mediated transcriptional regulation, growth arrest and apoptosis. We identify the functional Gas5-SR interface and generate point mutations that ablate the SR-Gas5 lincRNA interaction, altering Gas5-driven apoptosis in cancer cell lines. Further, we find that the Gas5 SR-recognition sequence is conserved among haplorhines, with its evolutionary origin as a splice acceptor site. This study demonstrates that lincRNAs can recognize protein targets in a conserved, sequence-specific manner in order to affect critical cell functions.
1] Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA [2] Discovery and Developmental Therapeutics, Winship Cancer Institute, Atlanta, Georgia 30322, USA.
William H
WH
Hudson
Institute of Science and Technology in Medicine, School of Life Sciences, Keele University, Keele ST5 5BG, UK.
Mark R
MR
Pickard
Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida 33458 USA.
Ian Mitchelle S
IM
de Vera
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Emily G
EG
Kuiper
Institute of Science and Technology in Medicine, School of Life Sciences, Keele University, Keele ST5 5BG, UK.
Mirna
M
Mourtada-Maarabouni
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Graeme L
GL
Conn
Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida 33458 USA.
Douglas J
DJ
Kojetin
Institute of Science and Technology in Medicine, School of Life Sciences, Keele University, Keele ST5 5BG, UK.
Gwyn T
GT
Williams
1] Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA [2] Discovery and Developmental Therapeutics, Winship Cancer Institute, Atlanta, Georgia 30322, USA.
Eric A
EA
Ortlund
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology*; D017124:Conserved Sequence; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000473:pathology; D062085:RNA, Long Noncoding / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020537:RNA, Small Nucleolar / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D020218:Response Elements / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*
D062085:RNA, Long Noncoding; D020537:RNA, Small Nucleolar; D011987:Receptors, Steroid; C109857:growth arrest specific transcript 5