title: A SUMO-regulated activation function controls synergy of c-Myb through a repressor-activator switch leading to differential p300 recruitment.
abstract: 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.
authors.affiliation: Department of Molecular Biosciences, University of Oslo, Oslo, Norway.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Molvaersmyr
authors.forename: Thomas
authors.initials: T
authors.lastname: Saether
authors.forename: Siv
authors.initials: S
authors.lastname: Gilfillan
authors.forename: Petra Isabel
authors.initials: PI
authors.lastname: Lorenzo
authors.forename: Heidi
authors.initials: H
authors.lastname: Kvaløy
authors.forename: Vilborg
authors.initials: V
authors.lastname: Matre
authors.forename: Odd Stokke
authors.initials: OS
authors.lastname: Gabrielsen
mesh_terms: 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*
chemical_list: 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
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