title: PHF1 Tudor and N-terminal domains synergistically target partially unwrapped nucleosomes to increase DNA accessibility.
abstract: The Tudor domain of human PHF1 recognizes trimethylated lysine 36 on histone H3 (H3K36me3). PHF1 relies on this interaction to regulate PRC2 methyltransferase activity, localize to DNA double strand breaks and mediate nucleosome accessibility. Here, we investigate the impact of the PHF1 N-terminal domain (NTD) on the Tudor domain interaction with the nucleosome. We show that the NTD is partially ordered when it is natively attached to the Tudor domain. Through a combination of FRET and single molecule studies, we find that the increase of DNA accessibility within the H3K36me3-containing nucleosome, instigated by the Tudor binding to H3K36me3, is dramatically enhanced by the NTD. We demonstrate that this nearly order of magnitude increase is due to preferential binding of PHF1 to partially unwrapped nucleosomes, and that PHF1 alters DNA-protein binding within the nucleosome by decreasing dissociation rates. These results highlight the potency of a PTM-binding protein to regulate DNA accessibility and underscores the role of the novel mechanism by which nucleosomes control DNA-protein binding through increasing protein dissociation rates.
authors.affiliation: Department of Physics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Gibson
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Jovylyn
authors.initials: J
authors.lastname: Gatchalian
authors.affiliation: Department of Physics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Slater
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
authors.affiliation: Department of Physics, Ohio State University, Columbus, OH 43210, USA.|Biophysics Graduate Program, Ohio State University, Columbus, OH 43210, USA.|Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Poirier
mesh_terms: D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D000071856:Tudor Domain
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D009707:Nucleosomes; C112309:PHF1 protein, human; D063146:Polycomb-Group Proteins; D004247:DNA