Back to Search
Start Over
ATM antagonizes NHEJ proteins assembly and DNA-ends synapsis at single-ended DNA double strand breaks.
- Source :
-
Nucleic acids research [Nucleic Acids Res] 2020 Sep 25; Vol. 48 (17), pp. 9710-9723. - Publication Year :
- 2020
-
Abstract
- 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.<br /> (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Subjects :
- Ataxia Telangiectasia Mutated Proteins genetics
Camptothecin pharmacology
Cell Line
DNA End-Joining Repair drug effects
DNA Ligase ATP genetics
DNA Ligase ATP metabolism
DNA, Single-Stranded
DNA-Activated Protein Kinase genetics
Humans
Ku Autoantigen genetics
MRE11 Homologue Protein genetics
MRE11 Homologue Protein metabolism
Phosphorylation
Topoisomerase I Inhibitors pharmacology
Ataxia Telangiectasia Mutated Proteins metabolism
DNA Breaks, Double-Stranded
DNA End-Joining Repair physiology
DNA-Activated Protein Kinase metabolism
Ku Autoantigen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1362-4962
- Volume :
- 48
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Nucleic acids research
- Publication Type :
- Academic Journal
- Accession number :
- 32890395
- Full Text :
- https://doi.org/10.1093/nar/gkaa723