Splicing regulates NAD metabolite binding to histone macroH2A
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Updated: Aug 7, 2026

Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
Published on: August 9, 2019
Georg Kustatscher1, Michael Hothorn, Céline Pugieux
1Gene Expression Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Abstract:
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.
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