Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair.pdf (5.68 MB)
Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair
journal contribution
posted on 2023-06-07, 07:45 authored by 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 CaldecottKeith CaldecottNeurodegeneration 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.
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Publication status
- Published
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- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Nature ResearchExternal DOI
Issue
1Volume
11Page range
1-13Article number
a3391Event location
EnglandDepartment affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2020-08-20First Open Access (FOA) Date
2020-08-20First Compliant Deposit (FCD) Date
2020-08-20Usage metrics
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