A SUMO-regulated activation function controls synergy of c-Myb through a repressor-activator switch leading to differential p300 recruitment.
Synergy between transcription factors operating together on complex promoters is a key aspect of gene activation. The ability of specific factors to synergize is restricted by sumoylation (synergy control, SC). Focusing on the haematopoietic transcription factor c-Myb, we found evidence for a strong SC linked to SUMO-conjugation in its negative regulatory domain (NRD), while AMV v-Myb has escaped this control. Mechanistic studies revealed a SUMO-dependent switch in the function of NRD. When NRD is sumoylated, the activity of c-Myb is reduced. When sumoylation is abolished, NRD switches into being activating, providing the factor with a second activation function (AF). Thus, c-Myb harbours two AFs, one that is constitutively active and one in the NRD being SUMO-regulated (SRAF). This double AF augments c-Myb synergy at compound natural promoters. A similar SUMO-dependent switch was observed in the regulatory domains of Sp3 and p53. We show that the change in synergy behaviour correlates with a SUMO-dependent differential recruitment of p300 and a corresponding local change in histone H3 and H4 acetylation. We therefore propose a general model for SUMO-mediated SC, where SUMO controls synergy by determining the number and strength of AFs associated with a promoter leading to differential chromatin signatures.
Molvaersmyr
Ann-Kristin
AK
Department of Molecular Biosciences, University of Oslo, Oslo, Norway.
Saether
Thomas
T
Gilfillan
Siv
S
Lorenzo
Petra Isabel
PI
Kvaløy
Heidi
H
Matre
Vilborg
V
Gabrielsen
Odd Stokke
OS
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*
D002843:Chromatin; D020598:Proto-Oncogene Proteins c-myb; D012097:Repressor Proteins; D025842:SUMO-1 Protein; D015534:Trans-Activators; D004247:DNA; D050881:E1A-Associated p300 Protein
Blood. 2002 Jan 15;99(2):576-83
11781241
Curr Opin Genet Dev. 2001 Apr;11(2):205-8
11250145
J Biol Chem. 2005 Jan 7;280(1):146-55
15507434
J Biol Chem. 2007 Dec 14;282(50):36155-66
17940278
Trends Biochem Sci. 1995 Dec;20(12):517-21
8571454
Mol Cell Biol. 1997 Sep;17(9):5127-35
9271390
Nucleic Acids Res. 2007;35(21):7237-47
17959653
Mol Cell. 2008 Mar 28;29(6):742-54
18374648
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15758-63
14663148
Nature. 2002 Oct 17;419(6908):738-43
12384703
Blood Cells Mol Dis. 2008 Mar-Apr;40(2):219-26
17950008
J Biol Chem. 2007 May 11;282(19):13994-4005
17344210
Nat Rev Mol Cell Biol. 2007 Dec;8(12):947-56
18000527
Eur J Biochem. 2003 Mar;270(6):1338-48
12631292
Oncogene. 2008 Aug 7;27(34):4644-56
18408764
Nature. 1995 Sep 21;377(6546):254-7
7675113
Nature. 2008 Apr 10;452(7188):709-11
18401402
Blood Cells Mol Dis. 2007 Nov-Dec;39(3):278-86
17587615
Mol Cell Biol. 1995 May;15(5):2437-47
7739528
EMBO J. 1996 Jun 3;15(11):2771-80
8654374
Nature. 1990 May 24;345(6273):361-4
2160609
Oncogene. 1999 May 13;18(19):3017-33
10378697
J Biol Chem. 2002 Mar 15;277(11):8999-9009
11779867
Biochem J. 2002 Nov 1;367(Pt 3):907-11
12144530
Mol Cell. 2004 Feb 27;13(4):611-7
14992729
J Biol Chem. 2006 Dec 29;281(52):40065-75
17077080
Epigenetics. 2009 Oct 1;4(7):440-4
19829068
Nat Rev Cancer. 2008 Jul;8(7):523-34
18574464
Mol Cell. 2003 Apr;11(4):1043-54
12718889
J Biol Chem. 1999 Jan 15;274(3):1189-92
9880483
Genes Dev. 1992 Dec;6(12B):2524-35
1340467
EMBO J. 1997 Jul 1;16(13):3924-34
9233802
EMBO J. 1996 Oct 15;15(20):5659-67
8896459
Mol Cell Biol. 2004 Dec;24(24):10529-41
15572661
Mol Endocrinol. 2004 Oct;18(10):2451-62
15192080
Mol Endocrinol. 2008 Sep;22(9):2061-75
18562626
Mol Cell Biol. 1995 Mar;15(3):1405-21
7862134
Mol Cell Biol. 2005 Jan;25(1):499-511
15601869
Mol Cell. 2009 Apr 24;34(2):145-54
19394292
Mol Cell Biol. 2000 Aug;20(16):6040-50
10913186
Cell. 2007 May 18;129(4):823-37
17512414
Genes Dev. 1993 May;7(5):749-59
7684005
Mol Cell Biol. 1996 May;16(5):2044-55
8628270
Mol Cell. 2007 Dec 14;28(5):823-37
18082607
Proc Natl Acad Sci U S A. 1989 Aug;86(15):5758-62
2668947
EMBO Rep. 2008 Sep;9(9):899-906
18617891
J Biol Chem. 1995 Apr 14;270(15):8763-71
7721782
Curr Opin Genet Dev. 2005 Oct;15(5):536-41
16095902
Genes Dev. 1996 Mar 1;10(5):528-40
8598284
EMBO J. 1993 May;12(5):2027-38
8491193
Nature. 1990 May 24;345(6273):359-61
2188137
J Biol Chem. 2003 Mar 14;278(11):9134-41
12511558
Mol Cell Biol. 1996 Sep;16(9):4717-25
8756629