Splicing regulates NAD metabolite binding to histone macroH2A.
Histone macroH2A is a hallmark of mammalian heterochromatin. Here we show that human macroH2A1.1 binds the SirT1-metabolite O-acetyl-ADP-ribose (OAADPR) through its macro domain. The 1.6-A crystal structure and mutants reveal how the metabolite is recognized. Mutually exclusive exon use in the gene H2AFY produces macroH2A1.2, whose tissue distribution differs. MacroH2A1.2 shows only subtle structural changes but cannot bind nucleotides. Alternative splicing may thus regulate the binding of nicotinamide adenine dinucleotide (NAD) metabolites to chromatin.
Kustatscher
Georg
G
Gene Expression Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Hothorn
Michael
M
Pugieux
Céline
C
Scheffzek
Klaus
K
Ladurner
Andreas G
AG
D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D003461:Crystallography; D040461:Gene Components; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism*; D038961:O-Acetyl-ADP-Ribose / Q000737:chemistry / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism
D006570:Heterochromatin; D006657:Histones; D038961:O-Acetyl-ADP-Ribose; C120756:macroH2A histone; D009243:NAD; D037761:Sirtuins