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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

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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 Caldecott
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Nature Communications

ISSN

2041-1723

Publisher

Nature Research

Issue

1

Volume

11

Page range

1-13

Article number

a3391

Event location

England

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2020-08-20

First Open Access (FOA) Date

2020-08-20

First Compliant Deposit (FCD) Date

2020-08-20

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