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

Abstract

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.

• 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
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 3391 (07 07 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32636369 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromatin
• Histones
• X-ray Repair Cross Complementing Protein 1
• XRCC1 protein, human
• Adenosine Diphosphate Ribose
• Glycoside Hydrolases
• ADPRS protein, human

Topics

• Adenosine Diphosphate Ribose (chemistry)
• Cell Line, Tumor
• Cell Survival
• Chromatin (chemistry)
• DNA Breaks, Single-Stranded
• DNA Repair
• Fibroblasts
• Gene Expression Regulation
• Gene Knockout Techniques
• Glycoside Hydrolases (genetics)
• HEK293 Cells
• Histones (chemistry)
• Humans
• Mutation
• Neurodegenerative Diseases (genetics)
• X-ray Repair Cross Complementing Protein 1 (genetics)