Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription.
With the recent recognition of non-coding RNAs (ncRNAs) flanking many genes, a central issue is to obtain a full understanding of their potential roles in regulated gene transcription programmes, possibly through different mechanisms. Here we show that an RNA-binding protein, TLS (for translocated in liposarcoma), serves as a key transcriptional regulatory sensor of DNA damage signals that, on the basis of its allosteric modulation by RNA, specifically binds to and inhibits CREB-binding protein (CBP) and p300 histone acetyltransferase activities on a repressed gene target, cyclin D1 (CCND1) in human cell lines. Recruitment of TLS to the CCND1 promoter to cause gene-specific repression is directed by single-stranded, low-copy-number ncRNA transcripts tethered to the 5' regulatory regions of CCND1 that are induced in response to DNA damage signals. Our data suggest that signal-induced ncRNAs localized to regulatory regions of transcription units can act cooperatively as selective ligands, recruiting and modulating the activities of distinct classes of RNA-binding co-regulators in response to specific signals, providing an unexpected ncRNA/RNA-binding protein-based strategy to integrate transcriptional programmes.
Howard Hughes Medical Institute.
Xiangting
X
Wang
Shigeki
S
Arai
Xiaoyuan
X
Song
Donna
D
Reichart
Kun
K
Du
Gabriel
G
Pascual
Paul
P
Tempst
Michael G
MG
Rosenfeld
Christopher K
CK
Glass
Riki
R
Kurokawa
D000494:Allosteric Regulation; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D016384:Consensus Sequence; D019938:Cyclin D1 / Q000235:genetics; D004249:DNA Damage; D015536:Down-Regulation; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009841:Oligonucleotides / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D009841:Oligonucleotides; D022661:RNA, Untranslated; D034702:RNA-Binding Protein FUS; D019938:Cyclin D1; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases