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

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 and Keith W. Caldecott ()
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Hana Hanzlikova: Institute of Molecular Genetics of the Czech Academy of Sciences
Evgeniia Prokhorova: University of Oxford
Katerina Krejcikova: Institute of Molecular Genetics of the Czech Academy of Sciences
Zuzana Cihlarova: Institute of Molecular Genetics of the Czech Academy of Sciences
Ilona Kalasova: Institute of Molecular Genetics of the Czech Academy of Sciences
Jan Kubovciak: Institute of Molecular Genetics of the Czech Academy of Sciences
Jana Sachova: Institute of Molecular Genetics of the Czech Academy of Sciences
Richard Hailstone: University of Sussex, Falmer
Jan Brazina: University of Sussex, Falmer
Shereen Ghosh: University of California, San Diego
Sebahattin Cirak: University of Cologne
Joseph G. Gleeson: University of California, San Diego
Ivan Ahel: University of Oxford
Keith W. Caldecott: Institute of Molecular Genetics of the Czech Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17069-9

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