Radiation-induced double-strand breaks require ATM but not Artemis for homologous recombination during S-phase.
Standard
Radiation-induced double-strand breaks require ATM but not Artemis for homologous recombination during S-phase. / Köcher, Sabrina; Rieckmann, Thorsten; Rohaly, Gabor; Mansour, Wael; Dikomey, Ekkehard; Dornreiter, Irena; Dahm-Daphi, Jochen.
in: NUCLEIC ACIDS RES, Jahrgang 40, Nr. 17, 17, 2012, S. 8336-8347.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Radiation-induced double-strand breaks require ATM but not Artemis for homologous recombination during S-phase.
AU - Köcher, Sabrina
AU - Rieckmann, Thorsten
AU - Rohaly, Gabor
AU - Mansour, Wael
AU - Dikomey, Ekkehard
AU - Dornreiter, Irena
AU - Dahm-Daphi, Jochen
PY - 2012
Y1 - 2012
N2 - Double-strand breaks (DSBs) are repaired by two distinct pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). The endonuclease Artemis and the PIK kinase Ataxia-Telangiectasia Mutated (ATM), mutated in prominent human radiosensitivity syndromes, are essential for repairing a subset of DSBs via NHEJ in G1 and HR in G2. Both proteins have been implicated in DNA end resection, a mandatory step preceding homology search and strand pairing in HR. Here, we show that during S-phase Artemis but not ATM is dispensable for HR of radiation-induced DSBs. In replicating AT cells, numerous Rad51 foci form gradually, indicating a Rad51 recruitment process that is independent of ATM-mediated end resection. Those DSBs decorated with Rad51 persisted through S- and G2-phase indicating incomplete HR resulting in unrepaired DSBs and a pronounced G2 arrest. We demonstrate that in AT cells loading of Rad51 depends on functional ATR/Chk1. The ATR-dependent checkpoint response is most likely activated when the replication fork encounters radiation-induced single-strand breaks leading to generation of long stretches of single-stranded DNA. Together, these results provide new insight into the role of ATM for initiation and completion of HR during S- and G2-phase. The DSB repair defect during S-phase significantly contributes to the radiosensitivity of AT cells.
AB - Double-strand breaks (DSBs) are repaired by two distinct pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). The endonuclease Artemis and the PIK kinase Ataxia-Telangiectasia Mutated (ATM), mutated in prominent human radiosensitivity syndromes, are essential for repairing a subset of DSBs via NHEJ in G1 and HR in G2. Both proteins have been implicated in DNA end resection, a mandatory step preceding homology search and strand pairing in HR. Here, we show that during S-phase Artemis but not ATM is dispensable for HR of radiation-induced DSBs. In replicating AT cells, numerous Rad51 foci form gradually, indicating a Rad51 recruitment process that is independent of ATM-mediated end resection. Those DSBs decorated with Rad51 persisted through S- and G2-phase indicating incomplete HR resulting in unrepaired DSBs and a pronounced G2 arrest. We demonstrate that in AT cells loading of Rad51 depends on functional ATR/Chk1. The ATR-dependent checkpoint response is most likely activated when the replication fork encounters radiation-induced single-strand breaks leading to generation of long stretches of single-stranded DNA. Together, these results provide new insight into the role of ATM for initiation and completion of HR during S- and G2-phase. The DSB repair defect during S-phase significantly contributes to the radiosensitivity of AT cells.
KW - Humans
KW - Cell Line
KW - Protein-Serine-Threonine Kinases/physiology
KW - Radiation Tolerance
KW - Cell Cycle/genetics/radiation effects
KW - Cell Cycle Proteins/physiology
KW - DNA Breaks, Double-Stranded
KW - DNA-Binding Proteins/physiology
KW - Nuclear Proteins/physiology
KW - Rad51 Recombinase/analysis
KW - Recombinational DNA Repair
KW - S Phase/genetics/radiation effects
KW - Tumor Suppressor Proteins/physiology
KW - Humans
KW - Cell Line
KW - Protein-Serine-Threonine Kinases/physiology
KW - Radiation Tolerance
KW - Cell Cycle/genetics/radiation effects
KW - Cell Cycle Proteins/physiology
KW - DNA Breaks, Double-Stranded
KW - DNA-Binding Proteins/physiology
KW - Nuclear Proteins/physiology
KW - Rad51 Recombinase/analysis
KW - Recombinational DNA Repair
KW - S Phase/genetics/radiation effects
KW - Tumor Suppressor Proteins/physiology
U2 - 10.1093/nar/gks604
DO - 10.1093/nar/gks604
M3 - SCORING: Journal article
VL - 40
SP - 8336
EP - 8347
JO - NUCLEIC ACIDS RES
JF - NUCLEIC ACIDS RES
SN - 0305-1048
IS - 17
M1 - 17
ER -
