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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,

. 2020 ; 11 (1) : 3391. [pub] 20200707

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20024897

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

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 Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair / $c H. Hanzlikova, E. Prokhorova, K. Krejcikova, Z. Cihlarova, I. Kalasova, J. Kubovciak, J. Sachova, R. Hailstone, J. Brazina, S. Ghosh, S. Cirak, JG. Gleeson, I. Ahel, KW. Caldecott,
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$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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