DNA repair: Kinetics and thresholds

Citation
Pj. O'Connor et al., DNA repair: Kinetics and thresholds, TOX PATHOL, 28(3), 2000, pp. 375-381
Citations number
48
Categorie Soggetti
Pharmacology & Toxicology
Journal title
TOXICOLOGIC PATHOLOGY
ISSN journal
01926233 → ACNP
Volume
28
Issue
3
Year of publication
2000
Pages
375 - 381
Database
ISI
SICI code
0192-6233(200005/06)28:3<375:DRKAT>2.0.ZU;2-X
Abstract
DNA damage is a critical factor in the initiation of chemically induced tox icities (including cancer), and the repair of this damage represents the ce ll'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 O-6-alkylguanine-DNA alkyltransferase (ATase) are used to illustrate how DNA repair can protect cells against alkylating age nt-induced toxicities, mutagenesis, clastogenesis, and carcinogenesis. The effectiveness of this repair protein can be measured based on its ability t o deplete levels of its promutagenic substrate O-6-methylguanine (O-6-meG) in the DNA of cells. These studies reveal that the repair of O-6-meG from D NA occurs heterogeneously, both intra- and intercellularly. Even in cells t hat repair O-6-meG hyperefficiently, certain regions of chromatin DNA are r epaired 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, so me cells are clearly repair deficient, because the O-6-meG can persist in D NA 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 homeostat ic control of DNA repair function in mammalian cells are not yet well under stood. Because there are now indications of the mechanisms by which the lev el of DNA damage may be sensed land so influence the activity of the ATase repair protein), this is an important area for future study.