Repair-deficient 3-methyladenine DNA glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation-induced chromosome damage and cell killing. 1996

B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

In Escherichia coli, the repair of 3-methyladenine (3MeA) DNA lesions prevents alkylation-induced cell death because unrepaired 3MeA blocks DNA replication. Whether this lesion is cytotoxic to mammalian cells has been difficult to establish in the absence of 3MeA repair-deficient cell lines. We previously isolated and characterized a mouse 3MeA DNA glycosylase cDNA (Aag) that provides resistance to killing by alkylating agents in E. coli. To determine the in vivo role of Aag, we cloned a large fragment of the Aag gene and used it to create Aag-deficient mouse cells by targeted homologous recombination. Aag null cells have no detectable Aag transcripts or 3MeA DNA glycosylase activity. The loss of Aag renders cells significantly more sensitive to methyl methanesulfonate-induced chromosome damage, and to cell killing induced by two methylating agents, one of which produces almost exclusively 3MeAs. Aag null embryonic stem cells become sensitive to two cancer chemotherapeutic alkylating agents, namely 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C, indicating that Aag status is an important determinant of cellular resistance to these agents. We conclude that this mammalian 3MeA DNA glycosylase plays a pivotal role in preventing alkylation-induced chromosome damage and cytotoxicity.

UI MeSH Term Description Entries
D009699 N-Glycosyl Hydrolases A class of enzymes involved in the hydrolysis of the N-glycosidic bond of nitrogen-linked sugars. Glycoside Hydrolases, Nitrogen-linked,Hydrolases, N-Glycosyl,Nucleosidase,Nucleosidases,Nucleoside Hydrolase,Nitrogen-linked Glycoside Hydrolases,Nucleoside Hydrolases,Glycoside Hydrolases, Nitrogen linked,Hydrolase, Nucleoside,Hydrolases, N Glycosyl,Hydrolases, Nitrogen-linked Glycoside,Hydrolases, Nucleoside,N Glycosyl Hydrolases,Nitrogen linked Glycoside Hydrolases
D002455 Cell Division The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION. M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004260 DNA Repair The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones. DNA Damage Response
D000477 Alkylating Agents Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. Alkylating Agent,Alkylator,Alkylators,Agent, Alkylating,Agents, Alkylating
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012854 Sister Chromatid Exchange An exchange of segments between the sister chromatids of a chromosome, either between the sister chromatids of a meiotic tetrad or between the sister chromatids of a duplicated somatic chromosome. Its frequency is increased by ultraviolet and ionizing radiation and other mutagenic agents and is particularly high in BLOOM SYNDROME. Chromatid Exchange, Sister,Chromatid Exchanges, Sister,Exchange, Sister Chromatid,Exchanges, Sister Chromatid,Sister Chromatid Exchanges
D014466 Ultraviolet Rays That portion of the electromagnetic spectrum immediately below the visible range and extending into the x-ray frequencies. The longer wavelengths (near-UV or biotic or vital rays) are necessary for the endogenous synthesis of vitamin D and are also called antirachitic rays; the shorter, ionizing wavelengths (far-UV or abiotic or extravital rays) are viricidal, bactericidal, mutagenic, and carcinogenic and are used as disinfectants. Actinic Rays,Black Light, Ultraviolet,UV Light,UV Radiation,Ultra-Violet Rays,Ultraviolet Light,Ultraviolet Radiation,Actinic Ray,Light, UV,Light, Ultraviolet,Radiation, UV,Radiation, Ultraviolet,Ray, Actinic,Ray, Ultra-Violet,Ray, Ultraviolet,Ultra Violet Rays,Ultra-Violet Ray,Ultraviolet Black Light,Ultraviolet Black Lights,Ultraviolet Radiations,Ultraviolet Ray
D016296 Mutagenesis Process of generating a genetic MUTATION. It may occur spontaneously or be induced by MUTAGENS. Mutageneses

Related Publications

B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
December 1979, Biochemical and biophysical research communications,
B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
September 2000, Nucleic acids research,
B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
May 2007, The EMBO journal,
B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
December 1990, The EMBO journal,
B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
February 2002, Cancer research,
B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
June 1980, Journal of molecular biology,
B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
January 2012, Toxicology letters,
B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
January 1995, Nucleic acids symposium series,
B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
July 1990, Mutation research,
B P Engelward, and A Dreslin, and J Christensen, and D Huszar, and C Kurahara, and L Samson
January 2015, PloS one,
Copied contents to your clipboard!