ATM antagonizes NHEJ proteins assembly and DNA-ends synapsis at single-ended DNA double strand breaks.
Ataxia Telangiectasia Mutated Proteins
/ genetics
Camptothecin
/ pharmacology
Cell Line
DNA Breaks, Double-Stranded
DNA End-Joining Repair
/ drug effects
DNA Ligase ATP
/ genetics
DNA, Single-Stranded
DNA-Activated Protein Kinase
/ genetics
Humans
Ku Autoantigen
/ genetics
MRE11 Homologue Protein
/ genetics
Phosphorylation
Topoisomerase I Inhibitors
/ pharmacology
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
25 09 2020
25 09 2020
Historique:
accepted:
21
08
2020
revised:
29
07
2020
received:
20
09
2019
pubmed:
6
9
2020
medline:
11
11
2020
entrez:
5
9
2020
Statut:
ppublish
Résumé
Two DNA repair pathways operate at DNA double strand breaks (DSBs): non-homologous end-joining (NHEJ), that requires two adjacent DNA ends for ligation, and homologous recombination (HR), that resects one DNA strand for invasion of a homologous duplex. Faithful repair of replicative single-ended DSBs (seDSBs) is mediated by HR, due to the lack of a second DNA end for end-joining. ATM stimulates resection at such breaks through multiple mechanisms including CtIP phosphorylation, which also promotes removal of the DNA-ends sensor and NHEJ protein Ku. Here, using a new method for imaging the recruitment of the Ku partner DNA-PKcs at DSBs, we uncover an unanticipated role of ATM in removing DNA-PKcs from seDSBs in human cells. Phosphorylation of DNA-PKcs on the ABCDE cluster is necessary not only for DNA-PKcs clearance but also for the subsequent MRE11/CtIP-dependent release of Ku from these breaks. We propose that at seDSBs, ATM activity is necessary for the release of both Ku and DNA-PKcs components of the NHEJ apparatus, and thereby prevents subsequent aberrant interactions between seDSBs accompanied by DNA-PKcs autophosphorylation and detrimental commitment to Lig4-dependent end-joining.
Identifiants
pubmed: 32890395
pii: 5901963
doi: 10.1093/nar/gkaa723
pmc: PMC7515714
doi:
Substances chimiques
DNA, Single-Stranded
0
LIG4 protein, human
0
MRE11 protein, human
0
Topoisomerase I Inhibitors
0
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
DNA-Activated Protein Kinase
EC 2.7.11.1
PRKDC protein, human
EC 2.7.11.1
MRE11 Homologue Protein
EC 3.1.-
XRCC5 protein, human
EC 3.6.4.12
Ku Autoantigen
EC 4.2.99.-
DNA Ligase ATP
EC 6.5.1.1
Camptothecin
XT3Z54Z28A
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9710-9723Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
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