Mammalian cells defective in DNA mismatch correction
- Clare Hall Labs., Herts (United Kingdom)
- Istituto Superiore di Sanita, Rome (Italy); and others
Mammalian cells counteract the cytotoxicity of methylating agents, including some used in antitumor chemotherapy, by removing the methylated base, O{sup 6}-methylguanine (O{sup 6}-meG) from their DNA. This removal is normally effected by a specific DNA repair enzyme (O{sup 6}-meG-DNA methyltransferase) that is expressed constitutively. In addition, an alternative type of resistance to methylating agents can be acquired after exposure of cells to the drug. This acquired resistance is highly specific for O{sup 6}-meG and is unusual in that alkylation of DNA is normal and there is no increase in the rate of repair of O{sup 6}-meG or any other damaged base. Instead, the cell is able to tolerate the presence of the usually cytotoxic O{sup 6}-meG and to replicate its DNA normally. The ambiguity of base pairing by O{sup 6}-meG and the observation that tolerant cells are also cross-resistant to the structurally similar 6-thioguanine in DNA has led to the suggestion that the cytotoxicity of O{sup 6}-meG (and 6-thioguanine) arises from ineffective attempts at DNA mismatch correction. This model postulates that tolerance arises as a consequence of loss of this important pathway.
- Research Organization:
- New York Academy of Sciences, New York, NY (United States)
- OSTI ID:
- 134876
- Report Number(s):
- CONF-9307221-; TRN: 95:007741-0043
- Resource Relation:
- Conference: DNA damage: effects on DNA structure and protein recognition, Burlington, VT (United States), 31 Jul - 4 Aug 1993; Other Information: PBD: 1994; Related Information: Is Part Of DNA damage: Effects on DNA structure and protein recognition; Wallace, S.S.; Van Houten, B.; Kow, Yoke Wah [eds.]; PB: 395 p.
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BASIC STUDIES
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
ANIMAL CELLS
GENETIC EFFECTS
CHEMOTHERAPY
MICROBIAL DRUG RESISTANCE
SPONTANEOUS MUTATIONS
BASES
METHYLATION
DNA
DNA REPAIR
DNA REPLICATION
STRUCTURE-ACTIVITY RELATIONSHIPS
METHYL TRANSFERASES
ENZYME ACTIVITY
AMINO ACIDS
SPECIFICITY
CHO CELLS
MUTATION FREQUENCY
TOXIC MATERIALS
PROTEINS
ELECTROPHORESIS
OLIGONUCLEOTIDES
DNA SEQUENCING
DNA-CLONING