title: Structural insights into the DNA-binding specificity of E2F family transcription factors.
abstract: The mammalian cell cycle is controlled by the E2F family of transcription factors. Typical E2Fs bind to DNA as heterodimers with the related dimerization partner (DP) proteins, whereas the atypical E2Fs, E2F7 and E2F8 contain two DNA-binding domains (DBDs) and act as repressors. To understand the mechanism of repression, we have resolved the structure of E2F8 in complex with DNA at atomic resolution. We find that the first and second DBDs of E2F8 resemble the DBDs of typical E2F and DP proteins, respectively. Using molecular dynamics simulations, biochemical affinity measurements and chromatin immunoprecipitation, we further show that both atypical and typical E2Fs bind to similar DNA sequences in vitro and in vivo. Our results represent the first crystal structure of an E2F protein with two DBDs, and reveal the mechanism by which atypical E2Fs can repress canonical E2F target genes and exert their negative influence on cell cycle progression.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83 Stockholm, Sweden.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Morgunova
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83 Stockholm, Sweden.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83 Stockholm, Sweden.
authors.forename: Arttu
authors.initials: A
authors.lastname: Jolma
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83 Stockholm, Sweden.
authors.forename: Kashyap
authors.initials: K
authors.lastname: Dave
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83 Stockholm, Sweden.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schmierer
authors.affiliation: European Synchrotron Radiation Facility, Division of Experiments, 38 000 Grenoble, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Popov
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, SE 106 91, Sweden.
authors.forename: Nadejda
authors.initials: N
authors.lastname: Eremina
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83 Stockholm, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Nilsson
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83 Stockholm, Sweden.|Genome-Scale Biology Research Program, Faculty of Medicine, University of Helsinki, PO Box 63, FI-00014 Helsinki, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
mesh_terms: D018360:Crystallography, X-Ray; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D005810:Multigene Family; D017434:Protein Structure, Tertiary; D013045:Species Specificity
chemical_list: D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004247:DNA