title: Multivalent Interactions by the Set8 Histone Methyltransferase With Its Nucleosome Substrate.
abstract: Set8 is the only mammalian monomethyltransferase responsible for H4K20me1, a methyl mark critical for genomic integrity of eukaryotic cells. We present here a structural model for how Set8 uses multivalent interactions to bind and methylate the nucleosome based on crystallographic and solution studies of the Set8/nucleosome complex. Our studies indicate that Set8 employs its i-SET and c-SET domains to engage nucleosomal DNA 1 to 1.5 turns from the nucleosomal dyad and in doing so, it positions the SET domain for catalysis with H4 Lys20. Surprisingly, we find that a basic N-terminal extension to the SET domain plays an even more prominent role in nucleosome binding, possibly by making an arginine anchor interaction with the nucleosome H2A/H2B acidic patch. We further show that proliferating cell nuclear antigen and the nucleosome compete for binding to Set8 through this basic extension, suggesting a mechanism for how nucleosome binding protects Set8 from proliferating cell nuclear antigen-dependent degradation during the cell cycle.
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Taverekere S
authors.initials: TS
authors.lastname: Girish
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: McGinty
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: sxt30@psu.edu.
authors.forename: Song
authors.initials: S
authors.lastname: Tan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry; D020134:Catalytic Domain; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry; D017353:Gene Deletion; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry; D009707:Nucleosomes / Q000737:chemistry*; D011485:Protein Binding; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry; D014981:Xenopus
chemical_list: D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D009707:Nucleosomes; C062521:RCC1 protein, human; D011994:Recombinant Proteins; D001120:Arginine; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human
keywords: SET domain; X-ray crystallography; chromatin biology; epigenetic; histone modifications