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Thresholds for Genotoxic Carcinogens

DNA Repair: Kinetics and Thresholds

Cancer Research Campaign Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 4BX, United Kingdom

Francis C.R. Manning

School of Biomedical Sciences, Nottingham University Medical School, Nottingham, NG2 2UH, United Kingdom, School of Biomolecular Sciences, Liverpool John Moores University, Liverpool, L3 3AF, United Kingdom

Anthony T. Gordon

School of Biomedical Sciences, Nottingham University Medical School, Nottingham, NG2 2UH, United Kingdom, Institute for Cancer Research, Royal Cancer Hospital, Sutton Surrey, SM2 5MG

Michael A. Billett

School of Biomedical Sciences, Nottingham University Medical School, Nottingham, NG2 2UH, United Kingdom

Donald P. Cooper

Cancer Research Campaign Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 4BX, United Kingdom, Micromass plc, Manchester, M23 9LZ, United Kingdom

Rhoderick H. Elder

Cancer Research Campaign Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 4BX, United Kingdom

Geoffrey P. Margison

Cancer Research Campaign Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 4BX, United Kingdom

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 06-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.

Key Words: DNA repair mechanisms • O6-methylguanine • O6-alkylguanine-DNA alkyltransferase • chromatin DNA • DNA repair-deficient DNA sequences • target cells

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