Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair

• DOI: 10.1038/s41467-020-17069-9
• Publication Date: 2020-07-07T10:04:08Z
• Authors: Hana Hanzlikova; Evgeniia Prokhorova; Katerina Krejcikova; Zuzana Cihlarova; Ilona Kalasova; Jan Kubovciak; Jana Sachova; Richard Hailstone; Jan Brazina; Shereen Ghosh; Sebahattin Cirak; Joseph G. Gleeson; Ivan Ahel; Keith W. Caldecott
• Keywords: Adenosine Diphosphate Ribose; 0303 health sciences; DNA Repair; Glycoside Hydrolases; Cell Survival; Science; Q; Neurodegenerative Diseases; Fibroblasts; Article; Chromatin; Histones; Gene Knockout Techniques; 03 medical and health sciences; HEK293 Cells; X-ray Repair Cross Complementing Protein 1; Gene Expression Regulation; Cell Line, Tumor; Mutation; Humans; DNA Breaks, Single-Stranded

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