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

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    Authors
    Johnson, Robert T
    Gotoh, Eisuke
    Mullinger, Ann M
    Ryan, Anderson J
    Shiloh, Yosef
    Ziv, Yael
    Squires, Shoshana
    Affiliation
    Department of Zoology, University of Cambridge, Downing Street, Cambridge, CB2 3EJ, United Kingdom. johnsort@umdnj.edu
    Issue Date
    1999-08-02
    
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    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.
    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
    URI
    http://hdl.handle.net/10541/91387
    DOI
    10.1006/bbrc.1999.1024
    PubMed ID
    10425184
    Type
    Article
    Language
    en
    ISSN
    0006-291X
    ae974a485f413a2113503eed53cd6c53
    10.1006/bbrc.1999.1024
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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