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Multiple direct interactions of TBP with the MYC oncoprotein
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. Univ Hlth Network, Canada; Struct Genom Consortium, Canada.
Univ Hlth Network, Canada; Univ Toronto, Canada.
Yokohama City Univ, Japan.
Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
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2019 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 26, no 11, p. 1035-+Article in journal (Refereed) Published
Abstract [en]

Transcription factor c-MYC is a potent oncoprotein; however, the mechanism of transcriptional regulation via MYC-protein interactions remains poorly understood. The TATA-binding protein (TBP) is an essential component of the transcription initiation complex TFIID and is required for gene expression. We identify two discrete regions mediating MYC-TBP interactions using structural, biochemical and cellular approaches. A 2.4 -angstrom resolution crystal structure reveals that human MYC amino acids 98-111 interact with TBP in the presence of the amino-terminal domain 1 of TBP-associated factor 1 (TAF1(TAND1)). Using biochemical approaches, we have shown that MYC amino acids 115-124 also interact with TBP independently of TAF1(TAND1). Modeling reveals that this region of MYC resembles a TBP anchor motif found in factors that regulate TBP promoter loading. Site-specific MYC mutants that abrogate MYC-TBP interaction compromise MYC activity. We propose that MYC-TBP interactions propagate transcription by modulating the energetic landscape of transcription initiation complex assembly.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 26, no 11, p. 1035-+
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-162549DOI: 10.1038/s41594-019-0321-zISI: 000495893200007PubMedID: 31686052OAI: oai:DiVA.org:liu-162549DiVA, id: diva2:1376274
Note

Funding Agencies|Swedish Science Council; Carl Trygger foundation; Swedish Child Cancer Foundation; Swedish Cancer Foundation; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR) [156167]; Linkoping University; University of TorontoUniversity of Toronto; SGC, a registered charity; AbbVie; Bayer Pharma AG; Boehringer IngelheimBoehringer Ingelheim; Canada Foundation for InnovationCanada Foundation for Innovation; Eshelman Institute for Innovation; Genome Canada through Ontario Genomics InstituteGenome Canada [OGI-055]; Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]; JanssenJohnson & Johnson USAJanssen Biotech Inc; Merck KGaA, Darmstadt, Germany; MSD; Novartis Pharma AG; Ontario Ministry of Research, Innovation and Science (MRIS); PfizerPfizer; Sao Paulo Research Foundation-FAPESPFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); TakedaTakeda Pharmaceutical Company Ltd; Wellcome; US Department of Energy, Office of Biological and Environmental ResearchUnited States Department of Energy (DOE) [DE-AC02-06CH11357]

Available from: 2019-12-09 Created: 2019-12-09 Last updated: 2019-12-09

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