Interplay of Histone Marks with Serine ADP-Ribosylation

Summary

Serine ADP-ribosylation (Ser-ADPr) is a recently discovered protein modification that is catalyzed by PARP1 and PARP2 when in complex with the eponymous histone PARylation factor 1 (HPF1). In addition to numerous other targets, core histone tails are primary acceptors of Ser-ADPr in the DNA damage response. Here, we show that specific canonical histone marks interfere with Ser-ADPr of neighboring residues and vice versa. Most notably, acetylation, but not methylation of H3K9, is mutually exclusive with ADPr of H3S10 in vitro and in vivo. We also broaden the O-linked ADPr spectrum by providing evidence for tyrosine ADPr on HPF1 and other proteins. Finally, we facilitate wider investigations into the interplay of histone marks with Ser-ADPr by introducing a simple approach for profiling posttranslationally modified peptides. Our findings implicate Ser-ADPr as a dynamic addition to the complex interplay of modifications that shape the histone code.

Graphical Abstract

Highlights

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  Histone serine ADP-ribosylation and proximal acetylation are mutually exclusive

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  PARP inhibitors block the DNA damage-induced histone H3 deacetylation

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  Tyrosine residues are ADP-ribosylation targets

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  Inverted polarity electrophoresis simplifies the study of histone marks

Abstract

Bartlett et al. demonstrate that serine ADP-ribosylation and proximal phosphorylation and acetylation are mutually exclusive at the N-terminal tails of core histones. They also expand the repertoire of ADP-ribosylation target residues by providing evidence for tyrosine ADP-ribosylation on HPF1 and several other proteins.