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Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair
H. Hanzlikova, E. Prokhorova, K. Krejcikova, Z. Cihlarova, I. Kalasova, J. Kubovciak, J. Sachova, R. Hailstone, J. Brazina, S. Ghosh, S. Cirak, JG. Gleeson, I. Ahel, KW. Caldecott,
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
C35050/A22284
Cancer Research UK - United Kingdom
T32 GM008666
NIGMS NIH HHS - United States
210634
Wellcome Trust - United Kingdom
MR/P010121/1
Medical Research Council - United Kingdom
101794
Wellcome Trust - United Kingdom
NLK
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- MeSH
- Adenosine Diphosphate Ribose chemistry MeSH
- Chromatin chemistry MeSH
- Fibroblasts MeSH
- Gene Knockout Techniques MeSH
- Glycoside Hydrolases genetics MeSH
- HEK293 Cells MeSH
- Histones chemistry MeSH
- DNA Breaks, Single-Stranded * MeSH
- Humans MeSH
- Mutation * MeSH
- Cell Line, Tumor MeSH
- Neurodegenerative Diseases genetics MeSH
- DNA Repair * MeSH
- X-ray Repair Cross Complementing Protein 1 genetics MeSH
- Gene Expression Regulation MeSH
- Cell Survival MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
References provided by Crossref.org
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- $a Hanzlikova, Hana $u Department of Genome Dynamics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague 4, 142 20, Czech Republic. hana.hanzlikova@img.cas.cz. Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9RQ, UK. hana.hanzlikova@img.cas.cz.
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- $a 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.
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