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    DNA repair: kinetics and thresholds.

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    Authors
    O'Connor, Peter J
    Manning, Francis C
    Gordon, Anthony T
    Billett, Michael A
    Cooper, Donald P
    Elder, Rhoderick H
    Margison, Geoffrey P
    Affiliation
    Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester, United Kingdom.
    Issue Date
    2000
    
    Metadata
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    Abstract
    DNA damage is a critical factor in the initiation of chemically induced toxicities (including cancer), and the repair of this damage represents the cell's first line of defense against the deleterious effects of these agents. The various mechanisms of DNA repair are reviewed briefly and the actions of the DNA repair protein O6-alkylguanine DNA alkyltransferase (ATase) are used to illustrate how DNA repair can protect cells against alkylating agent-induced toxicities, mutagenesis, clastogenesis, and carcinogenesis. The effectiveness of this repair protein can be measured based on its ability to deplete levels of its promutagenic substrate O6-methylguanine (O6-meG) in the DNA of cells. These studies reveal that the repair of O6-meG from DNA occurs heterogeneously, both intra- and intercellularly. Even in cells that repair O6-meG hyperefficiently, certain regions of chromatin DNA are repaired with difficulty, and in other regions they are not repaired at all; most likely this lack of repair is a result of the location of the lesion in the DNA sequence. When individual cells are compared within a tissue, some cells are clearly repair deficient, because the O6-meG can persist in DNA for many weeks, whereas in other cells, it is removed within a matter of hours. The role of these repair-deficient cells as targets for alkylating agent induced carcinogenesis is considered. The mechanisms of the homeostatic control of DNA repair function in mammalian cells are not yet well understood. Because there are now indications of the mechanisms by which the level of DNA damage may be sensed (and so influence the activity of the ATase repair protein), this is an important area for future study.
    Citation
    DNA repair: kinetics and thresholds., 28 (3):375-81 Toxicol Pathol
    Journal
    Toxicologic Pathology
    URI
    http://hdl.handle.net/10541/90041
    DOI
    10.1177/019262330002800304
    PubMed ID
    10862553
    Type
    Article
    Language
    en
    ISSN
    0192-6233
    ae974a485f413a2113503eed53cd6c53
    10.1177/019262330002800304
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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