An inducible long noncoding RNA amplifies DNA damage signaling.
Long noncoding RNAs (lncRNAs) are prevalent genes with frequently precise regulation but mostly unknown functions. Here we demonstrate that lncRNAs guide the organismal DNA damage response. DNA damage activated transcription of the DINO (Damage Induced Noncoding) lncRNA via p53. DINO was required for p53-dependent gene expression, cell cycle arrest and apoptosis in response to DNA damage, and DINO expression was sufficient to activate damage signaling and cell cycle arrest in the absence of DNA damage. DINO bound to p53 protein and promoted its stabilization, mediating a p53 auto-amplification loop. Dino knockout or promoter inactivation in mice dampened p53 signaling and ameliorated acute radiation syndrome in vivo. Thus, inducible lncRNA can create a feedback loop with its cognate transcription factor to amplify cellular signaling networks.
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.|Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA.
Adam M
AM
Schmitt
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
Julia T
JT
Garcia
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
Tiffany
T
Hung
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
Ryan A
RA
Flynn
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
Ying
Y
Shen
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
Kun
K
Qu
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USA.|Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.
Alexander Y
AY
Payumo
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
Ashwin
A
Peres-da-Silva
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
Daniela Kenzelmann
DK
Broz
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Rachel
R
Baum
Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, California, USA.
Shuling
S
Guo
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USA.|Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.
James K
JK
Chen
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
Laura D
LD
Attardi
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, California, USA.
Howard Y
HY
Chang
D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062085:RNA, Long Noncoding / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C000619299:DINOL lncRNA, human; D062085:RNA, Long Noncoding; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
J Cell Physiol. 2006 Oct;209(1):13-20
16741928
Genome Res. 2013 Feb;23(2):377-87
23064747
Dev Cell. 2003 Dec;5(6):903-14
14667412
Nat Commun. 2014 Dec 19;5:5812
25524025
Cancer Res. 1998 Dec 15;58(24):5637-9
9865712
Genome Biol. 2011 Jul 25;12(7):R67
21787385
Mol Cell. 2011 Sep 16;43(6):904-14
21925379
Nature. 2014 Mar 27;507(7493):462-70
24670764
RNA. 2005 Mar;11(3):344-54
15701734
J Biol Chem. 2007 Aug 24;282(34):24731-42
17569660
RNA. 2007 Nov;13(11):1825-33
17804642
Nat Cell Biol. 2003 Aug;5(8):741-7
12855956
Science. 2010 Jan 29;327(5965):593-6
20019247
Science. 2010 Aug 6;329(5992):689-93
20616235
BMC Bioinformatics. 2010 Mar 15;11:129
20230624
Curr Biol. 2003 Nov 11;13(22):1985-90
14614825
Nature. 2014 Mar 27;507(7493):455-61
24670763
Nature. 1993 Apr 29;362(6423):847-9
8479522
Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19248-53
20974908
Nat Biotechnol. 2011 Jun 01;29(7):607-14
21633356
Bioinformatics. 2009 Aug 15;25(16):2078-9
19505943
Nat Genet. 2003 Mar;33(3):396-400
12567186
J Clin Invest. 2010 Jul;120(7):2528-36
20577054
Cell Stem Cell. 2015 Jun 4;16(6):669-83
25936916
Oncogene. 1999 Dec 13;18(53):7644-55
10618704
Cancer Cell. 2003 Oct;4(4):321-8
14585359
Nucleic Acids Res. 2009 Jul;37(Web Server issue):W202-8
19458158
Nat Commun. 2014 Mar 18;5:3494
24637717
Genome Biol. 2008;9(9):R137
18798982
Cell. 2011 Dec 23;147(7):1537-50
22196729
Oncogene. 2004 Apr 22;23 (19):3265-71
15064735
RNA. 2009 Aug;15(8):1578-87
19535462
Cell. 2010 Jul 9;142(1):89-100
20598361
Nat Genet. 2011 Jun 05;43(7):621-9
21642992
Genome Biol. 2009;10(3):R25
19261174
Sci Signal. 2012 Jul 24;5(234):ra52
22827996
Genes Dev. 2013 May 1;27(9):1016-31
23651856
Genes Dev. 2016 Jan 15;30(2):191-207
26773003
Nat Protoc. 2006;1(3):1610-6
17406453
Mol Cell. 2014 Jun 5;54(5):777-90
24857549
Mol Cell. 2011 Nov 18;44(4):667-78
21963238
Nat Methods. 2013 Dec;10(12):1213-8
24097267
Cell Stem Cell. 2008 Jun 5;2(6):576-83
18522850
Nat Commun. 2015 Mar 27;6:6520
25813522
Cell. 2010 Aug 6;142(3):409-19
20673990