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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,
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
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
Directory of Open Access Journals
od 2015
Free Medical Journals
od 2010
Nature Open Access
od 2010-12-01
PubMed Central
od 2012
Europe PubMed Central
od 2012
ProQuest Central
od 2010-01-01
Open Access Digital Library
od 2015-01-01
Open Access Digital Library
od 2015-01-01
Medline Complete (EBSCOhost)
od 2012-11-01
Health & Medicine (ProQuest)
od 2010-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2010
Springer Nature OA/Free Journals
od 2010-12-01
- MeSH
- adenosindifosfát ribosa chemie MeSH
- chromatin chemie MeSH
- fibroblasty MeSH
- genový knockout MeSH
- glykosidhydrolasy genetika MeSH
- HEK293 buňky MeSH
- histony chemie MeSH
- jednořetězcové zlomy DNA * MeSH
- lidé MeSH
- mutace * MeSH
- nádorové buněčné linie MeSH
- neurodegenerativní nemoci genetika MeSH
- oprava DNA * MeSH
- protein XRCC1 genetika MeSH
- regulace genové exprese MeSH
- viabilita buněk MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
Citace poskytuje 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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