Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease.
ADP-ribosylation
ARH3/ADPRHL2
BRCA
DNA damage
PARG
PARP inhibitor
cancer
chromatin
neurodegeneration
telomere
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
17 06 2021
17 06 2021
Historique:
received:
04
08
2020
revised:
25
02
2021
accepted:
29
04
2021
pubmed:
22
5
2021
medline:
21
7
2021
entrez:
21
5
2021
Statut:
ppublish
Résumé
ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions in vivo remain unclear. ARH3 is the only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but is much less efficient than PARG against poly(ADP-ribose) (PAR) chains in vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout the cell cycle, including mitosis, and is surprisingly well tolerated. Conversely, persistent PARylation is highly toxic and has distinct physiological effects, in particular on active transcription histone marks such as H3K9ac and H3K27ac. Furthermore, we reveal a synthetic lethal interaction between ARH3 and PARG and identify loss of ARH3 as a mechanism of PARP inhibitor resistance, both of which can be exploited in cancer therapy. Finally, we extend our findings to neurodegeneration, suggesting that patients with inherited ARH3 deficiency suffer from stress-induced pathogenic increase in PARylation that can be mitigated by PARP inhibition.
Identifiants
pubmed: 34019811
pii: S1097-2765(21)00357-9
doi: 10.1016/j.molcel.2021.04.028
pmc: PMC8221567
mid: NIHMS1709114
pii:
doi:
Substances chimiques
Chromatin
0
Adenosine Diphosphate Ribose
20762-30-5
Poly Adenosine Diphosphate Ribose
26656-46-2
DNA
9007-49-2
Glycoside Hydrolases
EC 3.2.1.-
ADPRS protein, human
EC 3.2.1.143
poly ADP-ribose glycohydrolase
EC 3.2.1.143
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2640-2655.e8Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R016836/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Organisme : Wellcome Trust
ID : 203141/Z/16/Z
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R007195/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C35050/A22284
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 210634
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400653
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 210641/Z/18/Z
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA207209
Pays : United States
Organisme : Wellcome Trust
ID : 101794
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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