Universität zu Köln

Hanzlikova, Hana ORCID: 0000-0001-7235-7269, Prokhorova, Evgeniia ORCID: 0000-0002-5467-5586, Krejcikova, Katerina, Cihlarova, Zuzana, Kalasova, Ilona, Kubovciak, Jan, Sachova, Jana ORCID: 0000-0003-1176-6127, Hailstone, Richard, Brazina, Jan, Ghosh, Shereen, Cirak, Sebahattin, Gleeson, Joseph G., Ahel, Ivan and Caldecott, Keith W. (2020). Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hanzlikova, Hana UNSPECIFIED orcid.org/0000-0001-7235-7269 UNSPECIFIED Prokhorova, Evgeniia UNSPECIFIED orcid.org/0000-0002-5467-5586 UNSPECIFIED Krejcikova, Katerina UNSPECIFIED UNSPECIFIED UNSPECIFIED Cihlarova, Zuzana UNSPECIFIED UNSPECIFIED UNSPECIFIED Kalasova, Ilona UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubovciak, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachova, Jana UNSPECIFIED orcid.org/0000-0003-1176-6127 UNSPECIFIED Hailstone, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Brazina, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ghosh, Shereen UNSPECIFIED UNSPECIFIED UNSPECIFIED Cirak, Sebahattin UNSPECIFIED UNSPECIFIED UNSPECIFIED Gleeson, Joseph G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ahel, Ivan UNSPECIFIED UNSPECIFIED UNSPECIFIED Caldecott, Keith W. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-326825
DOI:	10.1038/s41467-020-17069-9
Journal or Publication Title:	Nat. Commun.
Volume:	11
Number:	1
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language POLY(ADP-RIBOSE) GLYCOHYDROLASE; XRCC1; BINDING; IDENTIFICATION; RIBOSYLATION; DEGRADATION; SPECIFICITY; SERINE; ATAXIA; ROLES Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32682