Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair.
Adenosine Diphosphate Ribose
/ chemistry
Cell Line, Tumor
Cell Survival
Chromatin
/ chemistry
DNA Breaks, Single-Stranded
DNA Repair
Fibroblasts
Gene Expression Regulation
Gene Knockout Techniques
Glycoside Hydrolases
/ genetics
HEK293 Cells
Histones
/ chemistry
Humans
Mutation
Neurodegenerative Diseases
/ genetics
X-ray Repair Cross Complementing Protein 1
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 07 2020
07 07 2020
Historique:
received:
29
01
2020
accepted:
08
06
2020
entrez:
9
7
2020
pubmed:
9
7
2020
medline:
9
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32636369
doi: 10.1038/s41467-020-17069-9
pii: 10.1038/s41467-020-17069-9
pmc: PMC7341855
doi:
Substances chimiques
Chromatin
0
Histones
0
X-ray Repair Cross Complementing Protein 1
0
XRCC1 protein, human
0
Adenosine Diphosphate Ribose
20762-30-5
Glycoside Hydrolases
EC 3.2.1.-
ADPRS protein, human
EC 3.2.1.143
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3391Subventions
Organisme : Cancer Research UK
ID : C35050/A22284
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : T32 GM008666
Pays : United States
Organisme : Wellcome Trust
ID : 210634
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P010121/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 101794
Pays : United Kingdom
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