KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs.
Acetylation
Cell Line, Tumor
Chromatin
/ genetics
Cyclin-Dependent Kinase 9
/ metabolism
Gene Expression Regulation
/ genetics
Histones
/ metabolism
Humans
Oncogenes
/ genetics
Promoter Regions, Genetic
/ genetics
Protein Processing, Post-Translational
/ genetics
RNA Polymerase II
/ genetics
Smad2 Protein
/ metabolism
Transcription Factors
/ metabolism
Transcription, Genetic
Tripartite Motif-Containing Protein 28
/ genetics
CDK9
KAP1
RNA polymerase II
SMAD
TGF-β
TRIM28
cancer
chromatin reader
epigenetics
pausing
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 06 2020
18 06 2020
Historique:
received:
02
10
2019
revised:
25
02
2020
accepted:
17
04
2020
pubmed:
14
5
2020
medline:
17
9
2020
entrez:
14
5
2020
Statut:
ppublish
Résumé
Precise control of the RNA polymerase II (RNA Pol II) cycle, including pausing and pause release, maintains transcriptional homeostasis and organismal functions. Despite previous work to understand individual transcription steps, we reveal a mechanism that integrates RNA Pol II cycle transitions. Surprisingly, KAP1/TRIM28 uses a previously uncharacterized chromatin reader cassette to bind hypo-acetylated histone 4 tails at promoters, guaranteeing continuous progression of RNA Pol II entry to and exit from the pause state. Upon chromatin docking, KAP1 first associates with RNA Pol II and then recruits a pathway-specific transcription factor (SMAD2) in response to cognate ligands, enabling gene-selective CDK9-dependent pause release. This coupling mechanism is exploited by tumor cells to aberrantly sustain transcriptional programs commonly dysregulated in cancer patients. The discovery of a factor integrating transcription steps expands the functional repertoire by which chromatin readers operate and provides mechanistic understanding of transcription regulation, offering alternative therapeutic opportunities to target transcriptional dysregulation.
Identifiants
pubmed: 32402252
pii: S1097-2765(20)30266-5
doi: 10.1016/j.molcel.2020.04.024
pmc: PMC7305985
mid: NIHMS1589061
pii:
doi:
Substances chimiques
Chromatin
0
Histones
0
SMAD2 protein, human
0
Smad2 Protein
0
Transcription Factors
0
TRIM28 protein, human
EC 2.3.2.27
Tripartite Motif-Containing Protein 28
EC 2.3.2.27
CDK9 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 9
EC 2.7.11.22
RNA Polymerase II
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1133-1151.e14Subventions
Organisme : NCI NIH HHS
ID : R01 CA252707
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM135671
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI114362
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251698
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL151334
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG067664
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
Références
Mol Cell. 2016 Jan 7;61(1):39-53
pubmed: 26725010
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Gastroenterology. 2010 Mar;138(3):1012-21.e1-5
pubmed: 19962984
Mol Cancer. 2017 Jul 6;16(1):116
pubmed: 28683746
J Mol Biol. 2002 Jul 12;320(3):629-44
pubmed: 12096914
Nat Rev Mol Cell Biol. 2018 Jul;19(7):419-435
pubmed: 29643418
J Mol Biol. 2000 Feb 4;295(5):1139-62
pubmed: 10653693
Nat Protoc. 2006;1(4):2088-90
pubmed: 17487199
Genes Dev. 2000 Apr 1;14(7):792-803
pubmed: 10766736
Nucleic Acids Res. 2012 Sep 1;40(17):e128
pubmed: 22610855
Cell. 2011 Dec 23;147(7):1511-24
pubmed: 22196728
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Nature. 2010 Dec 16;468(7326):927-32
pubmed: 21164480
Mol Cell. 2015 Apr 16;58(2):311-322
pubmed: 25773599
Cell. 1999 Apr 2;97(1):41-51
pubmed: 10199401
Genes Dev. 1996 Aug 15;10(16):2067-78
pubmed: 8769649
Mol Cell Biol. 2006 Nov;26(22):8623-38
pubmed: 16954381
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
Oncogene. 2017 May 25;36(21):2991-3001
pubmed: 28068325
Mol Cell. 2001 Aug;8(2):327-37
pubmed: 11545735
Cell. 2010 Apr 30;141(3):432-45
pubmed: 20434984
Nature. 2011 Dec 21;481(7381):365-70
pubmed: 22190034
J Biol Chem. 2014 Mar 28;289(13):9304-19
pubmed: 24497639
Nucleic Acids Res. 2016 Jun 2;44(10):4625-35
pubmed: 26861626
Nat Commun. 2018 Nov 27;9(1):5007
pubmed: 30479348
Sci Rep. 2019 Oct 30;9(1):15575
pubmed: 31666584
Cold Spring Harb Perspect Biol. 2016 Oct 3;8(10):
pubmed: 27449814
Mol Carcinog. 2018 Oct;57(10):1396-1407
pubmed: 29917268
Mol Cell Biol. 1999 Jun;19(6):4366-78
pubmed: 10330177
Mol Cell. 2010 Sep 24;39(6):963-74
pubmed: 20864041
Nature. 2002 Apr 4;416(6880):499-506
pubmed: 11932736
Cell. 2011 May 27;145(5):692-706
pubmed: 21596426
EMBO J. 1999 Nov 15;18(22):6385-95
pubmed: 10562550
J Biol Chem. 1998 Dec 18;273(51):34444-53
pubmed: 9852112
Stem Cells. 2017 Jan;35(1):147-157
pubmed: 27350605
J Proteome Res. 2009 Feb;8(2):583-94
pubmed: 19086899
Nature. 2017 Jul 20;547(7663):355-359
pubmed: 28678782
Nat Rev Genet. 2016 Aug;17(8):487-500
pubmed: 27346641
Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30
pubmed: 22992590
Genes Dev. 2015 Jan 1;29(1):39-47
pubmed: 25561494
Bioinformatics. 2004 Nov 22;20(17):3246-8
pubmed: 15180930
Nat Struct Mol Biol. 2010 Jul;17(7):815-21
pubmed: 20562857
Cancer Epidemiol. 2013 Feb;37(1):71-8
pubmed: 22959342
EMBO J. 1998 Dec 15;17(24):7395-403
pubmed: 9857195
Mol Cell. 2016 Jan 21;61(2):297-304
pubmed: 26799764
Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7923-7
pubmed: 8367444
Nature. 2006 Jul 6;442(7098):100-3
pubmed: 16728977
Cell Stem Cell. 2014 Nov 6;15(5):574-88
pubmed: 25312495
Nature. 2012 Mar 14;483(7389):286-7
pubmed: 22422261
Genes Dev. 2001 Feb 15;15(4):428-43
pubmed: 11230151
Cell Res. 2009 Feb;19(2):156-72
pubmed: 19153598
Mol Cell Biol. 2014 Jun;34(11):2075-91
pubmed: 24687849
Cell. 2016 Jan 28;164(3):353-64
pubmed: 26824653
Genes Dev. 2003 Jun 1;17(11):1402-14
pubmed: 12782658
Cell. 2017 Mar 9;168(6):960-976
pubmed: 28283069
Genes Dev. 2011 Apr 1;25(7):661-72
pubmed: 21460034
Mol Cell. 2011 Jul 8;43(1):85-96
pubmed: 21726812
PLoS One. 2014 Jul 01;9(7):e101040
pubmed: 24983967
Cell Rep. 2018 Apr 17;23(3):796-807
pubmed: 29669285
Nat Struct Mol Biol. 2008 Jun;15(6):626-33
pubmed: 18488044
Science. 2007 Dec 14;318(5857):1780-2
pubmed: 18079404
Mol Cell. 2004 Jan 16;13(1):67-76
pubmed: 14731395
Nucleic Acids Res. 2018 Jan 4;46(D1):D252-D259
pubmed: 29140464
Nat Genet. 2007 Dec;39(12):1507-11
pubmed: 17994021
Cancer Cell. 2012 Nov 13;22(5):571-84
pubmed: 23153532
Int J Mol Sci. 2014 Dec 26;16(1):363-77
pubmed: 25548895
Nature. 2001 Nov 15;414(6861):322-5
pubmed: 11713533
Nat Genet. 2007 Dec;39(12):1512-6
pubmed: 17994019
Cell. 2008 Jul 25;134(2):215-30
pubmed: 18662538
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Nat Struct Mol Biol. 2014 Oct;21(10):876-83
pubmed: 25173174
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Life Sci Alliance. 2019 Aug 19;2(4):
pubmed: 31427381
Acta Oncol. 2012 Mar;51(3):394-6
pubmed: 22268577
Trends Biochem Sci. 2013 Dec;38(12):603-11
pubmed: 24120742
Nat Genet. 2017 Jul;49(7):1045-1051
pubmed: 28504701
J Biol Chem. 1998 May 29;273(22):13855-60
pubmed: 9593731
Genes Dev. 1998 Feb 1;12(3):343-56
pubmed: 9450929
Cell. 2010 Nov 12;143(4):540-51
pubmed: 21074046
Nature. 2006 Jul 6;442(7098):91-5
pubmed: 16728978
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Crit Rev Biochem Mol Biol. 2006 May-Jun;41(3):105-78
pubmed: 16858867
Genes Dev. 2006 Mar 1;20(5):601-12
pubmed: 16510875
Mol Cell. 2007 Dec 14;28(5):823-37
pubmed: 18082607
Mol Cell. 2013 Nov 21;52(4):517-28
pubmed: 24184211
Science. 2010 Jan 15;327(5963):335-8
pubmed: 20007866
EMBO J. 2001 Jan 15;20(1-2):165-77
pubmed: 11226167
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
Nat Struct Mol Biol. 2007 Nov;14(11):1025-1040
pubmed: 17984965
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
Nat Rev Mol Cell Biol. 2018 Jul;19(7):464-478
pubmed: 29740129
Mol Cell. 2006 Jan 20;21(2):227-37
pubmed: 16427012
Chem Rev. 2013 Nov 13;113(11):8456-90
pubmed: 23952966
Nat Struct Mol Biol. 2012 Dec;19(12):1218-27
pubmed: 23211769
World J Surg Oncol. 2013 Apr 02;11:81
pubmed: 23548070
Nature. 2001 Nov 15;414(6861):317-22
pubmed: 11713532
Elife. 2017 Oct 10;6:
pubmed: 28994650
Cell Rep. 2012 Oct 25;2(4):1025-35
pubmed: 23062713
Cell. 2013 Dec 19;155(7):1581-1595
pubmed: 24360279
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10926-31
pubmed: 20508149
Genes Dev. 2008 Jul 15;22(14):1921-33
pubmed: 18628398
J Biol Chem. 1996 Oct 25;271(43):27176-83
pubmed: 8900211
Nat Biotechnol. 2011 May;29(5):436-42
pubmed: 21516085
Nat Biotechnol. 2014 Sep;32(9):896-902
pubmed: 25150836
Science. 2006 Feb 10;311(5762):844-7
pubmed: 16469925
Sci Rep. 2017 Oct 6;7(1):12782
pubmed: 28986585
Int J Clin Oncol. 2016 Oct;21(5):927-933
pubmed: 27095111
Cell Rep. 2012 Dec 27;2(6):1670-83
pubmed: 23260668
PLoS One. 2016 Nov 22;11(11):e0166438
pubmed: 27875550
Cell. 2011 Jul 8;146(1):92-104
pubmed: 21729782
Cell Host Microbe. 2015 Dec 9;18(6):723-35
pubmed: 26651948
Mol Cell Biol. 2015 Nov;35(22):3810-28
pubmed: 26324325
Nucleic Acids Res. 2009 Jul;37(Web Server issue):W202-8
pubmed: 19458158
Genes Dev. 2018 Sep 1;32(17-18):1215-1225
pubmed: 30150253
Proteins. 2010 Jun;78(8):1950-8
pubmed: 20408171
Cell Rep. 2014 Nov 6;9(3):1163-70
pubmed: 25437568
Mol Cell Biol. 1999 Jan;19(1):194-204
pubmed: 9858544
EMBO J. 2006 Oct 4;25(19):4490-502
pubmed: 16990801
Proc Natl Acad Sci U S A. 2011 May 17;108(20):8212-7
pubmed: 21531907
Genes Dev. 2001 Dec 15;15(24):3319-29
pubmed: 11751637