Neurodegeneration is a common hallmark of individuals with hereditary defects in DNA single-strand break repair; a process regulated by poly(ADP-ribose) metabolism. Recently, mutations in the ARH3 (ADPRHL2) hydrolase that removes ADP-ribose from proteins have been associated with neurodegenerative disease. Here, we show that ARH3-mutated patient cells accumulate mono(ADP-ribose) scars on core histones that are a molecular memory of recently repaired DNA single-strand breaks. We demonstrate that the ADP-ribose chromatin scars result in reduced endogenous levels of important chromatin modifications such as H3K9 acetylation, and that ARH3 patient cells exhibit measurable levels of deregulated transcription. Moreover, we show that the mono(ADP-ribose) scars are lost from the chromatin of ARH3-defective cells in the prolonged presence of PARP inhibition, and concomitantly that chromatin acetylation is restored to normal. Collectively, these data indicate that ARH3 can act as an eraser of ADP-ribose chromatin scars at sites of PARP activity during DNA single-strand break repair.

Center for Molecular Medicine Cologne University of Cologne Cologne 50931 Germany Department of Pediatrics Faculty of Medicine and University Hospital Cologne University of Cologne Cologne 50931 Germany Center for Rare Diseases Faculty of Medicine and University Hospital Cologne University of Cologne Cologne 50931 Germany

Department of Genome Dynamics Institute of Molecular Genetics of the Czech Academy of Sciences Prague 4 142 20 Czech Republic

Department of Genome Dynamics Institute of Molecular Genetics of the Czech Academy of Sciences Prague 4 142 20 Czech Republic Genome Damage and Stability Centre School of Life Sciences University of Sussex Falmer Brighton BN1 9RQ UK

Department of Genomics and Bioinformatics Institute of Molecular Genetics of the Czech Academy of Sciences Prague 4 142 20 Czech Republic

Genome Damage and Stability Centre School of Life Sciences University of Sussex Falmer Brighton BN1 9RQ UK

Laboratory for Pediatric Brain Disease Howard Hughes Medical Institute University of California San Diego La Jolla CA 92093 USA Rady Children's Institute for Genomic Medicine Rady Children's Hospital San Diego CA 92123 USA

Sir William Dunn School of Pathology University of Oxford Oxford OX1 3RE UK

References provided by Crossref.org