Targeting double-strand breaks to replicating DNA identifies a subpathway of DSB repair that is defective in ataxia-telangiectasia cells.

2.50
Hdl Handle:
http://hdl.handle.net/10541/91387
Title:
Targeting double-strand breaks to replicating DNA identifies a subpathway of DSB repair that is defective in ataxia-telangiectasia cells.
Authors:
Johnson, Robert T; Gotoh, Eisuke; Mullinger, Ann M; Ryan, Anderson J; Shiloh, Yosef; Ziv, Yael; Squires, Shoshana
Abstract:
The critical cellular defect(s) and basis for cell killing by ionizing radiation in ataxia-telangiectasia (A-T) are unknown. We use the topoisomerase I inhibitor camptothecin (CPT), which kills mainly S-phase cells and induces DSBs predominantly in replication forks, to show that A-T cells are defective in the repair of this particular subclass of DSBs. CPT-treated A-T cells reaching G2 have abnormally high levels of chromatid exchanges (viewed as prematurely condensed G2 chromosomes); aberrations in normal cells are mostly chromatid breaks. Transfectants of A-T cells with the wild-type ATM cDNA are corrected for CPT sensitivity, chromatid aberrations, and the DSB repair defect. These data suggest that in normal cells ATM, the A-T protein, probably recognizes DSBs in active replicons and targets the repair machinery to the breaks; in addition, the ATM protein is involved in the suppression of low-fidelity, adventitious rejoining between replication-associated DSBs. The loss of ATM functions therefore leads to genome destabilization, sensitivity to DSB-inducing agents and to the cancer-promoting illegitimate exchange events that follow.
Affiliation:
Department of Zoology, University of Cambridge, Downing Street, Cambridge, CB2 3EJ, United Kingdom. johnsort@umdnj.edu
Citation:
Targeting double-strand breaks to replicating DNA identifies a subpathway of DSB repair that is defective in ataxia-telangiectasia cells. 1999, 261 (2):317-25 Biochem. Biophys. Res. Commun.
Journal:
Biochemical and Biophysical Research Communications
Issue Date:
2-Aug-1999
URI:
http://hdl.handle.net/10541/91387
DOI:
10.1006/bbrc.1999.1024
PubMed ID:
10425184
Type:
Article
Language:
en
ISSN:
0006-291X
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorJohnson, Robert Ten
dc.contributor.authorGotoh, Eisukeen
dc.contributor.authorMullinger, Ann Men
dc.contributor.authorRyan, Anderson Jen
dc.contributor.authorShiloh, Yosefen
dc.contributor.authorZiv, Yaelen
dc.contributor.authorSquires, Shoshanaen
dc.date.accessioned2010-02-08T13:20:29Z-
dc.date.available2010-02-08T13:20:29Z-
dc.date.issued1999-08-02-
dc.identifier.citationTargeting double-strand breaks to replicating DNA identifies a subpathway of DSB repair that is defective in ataxia-telangiectasia cells. 1999, 261 (2):317-25 Biochem. Biophys. Res. Commun.en
dc.identifier.issn0006-291X-
dc.identifier.pmid10425184-
dc.identifier.doi10.1006/bbrc.1999.1024-
dc.identifier.urihttp://hdl.handle.net/10541/91387-
dc.description.abstractThe critical cellular defect(s) and basis for cell killing by ionizing radiation in ataxia-telangiectasia (A-T) are unknown. We use the topoisomerase I inhibitor camptothecin (CPT), which kills mainly S-phase cells and induces DSBs predominantly in replication forks, to show that A-T cells are defective in the repair of this particular subclass of DSBs. CPT-treated A-T cells reaching G2 have abnormally high levels of chromatid exchanges (viewed as prematurely condensed G2 chromosomes); aberrations in normal cells are mostly chromatid breaks. Transfectants of A-T cells with the wild-type ATM cDNA are corrected for CPT sensitivity, chromatid aberrations, and the DSB repair defect. These data suggest that in normal cells ATM, the A-T protein, probably recognizes DSBs in active replicons and targets the repair machinery to the breaks; in addition, the ATM protein is involved in the suppression of low-fidelity, adventitious rejoining between replication-associated DSBs. The loss of ATM functions therefore leads to genome destabilization, sensitivity to DSB-inducing agents and to the cancer-promoting illegitimate exchange events that follow.en
dc.language.isoenen
dc.subjectTumour Suppressor Proteinsen
dc.subject.meshAtaxia Telangiectasia-
dc.subject.meshCamptothecin-
dc.subject.meshCell Cycle-
dc.subject.meshCell Cycle Proteins-
dc.subject.meshCell Line-
dc.subject.meshCell Survival-
dc.subject.meshDNA Damage-
dc.subject.meshDNA Repair-
dc.subject.meshDNA Replication-
dc.subject.meshDNA Topoisomerases, Type I-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshHumans-
dc.subject.meshProtein-Serine-Threonine Kinases-
dc.subject.meshProteins-
dc.subject.meshRecombinant Proteins-
dc.subject.meshRecombination, Genetic-
dc.subject.meshSister Chromatid Exchange-
dc.subject.meshTransfection-
dc.subject.meshTumor Suppressor Proteins-
dc.titleTargeting double-strand breaks to replicating DNA identifies a subpathway of DSB repair that is defective in ataxia-telangiectasia cells.en
dc.typeArticleen
dc.contributor.departmentDepartment of Zoology, University of Cambridge, Downing Street, Cambridge, CB2 3EJ, United Kingdom. johnsort@umdnj.eduen
dc.identifier.journalBiochemical and Biophysical Research Communicationsen
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