Alkylpurine-DNA-N-glycosylase knockout mice show increased susceptibility to induction of mutations by methyl methanesulfonate.
AuthorsElder, Rhoderick H
Jansen, J G
Weeks, Robert J
Watson, Amanda J
Mynett, Kurt J
Cooper, Donald P
Rafferty, Joseph A
Heeran, Mel C
Wijnhoven, S W
Van Zeeland, A A
Margison, Geoffrey P
AffiliationCRC Section of Genome Damage and Repair, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 4BX, United Kingdom. RElder@picr.man.ac.uk
MetadataShow full item record
AbstractAlkylpurine-DNA-N-glycosylase (APNG) null mice have been generated by homologous recombination in embryonic stem cells. The null status of the animals was confirmed at the mRNA level by reverse transcription-PCR and by the inability of cell extracts of tissues from the knockout (ko) animals to release 3-methyladenine (3-meA) or 7-methylguanine (7-meG) from 3H-methylated calf thymus DNA in vitro. Following treatment with DNA-methylating agents, increased persistence of 7-meG was found in liver sections of APNG ko mice in comparison with wild-type (wt) mice, demonstrating an in vivo phenotype for the APNG null animals. Unlike other null mutants of the base excision repair pathway, the APNG ko mice exhibit a very mild phenotype, show no outward abnormalities, are fertile, and have an apparently normal life span. Neither a difference in the number of leukocytes in peripheral blood nor a difference in the number of bone marrow polychromatic erythrocytes was found when ko and wt mice were exposed to methylating or chloroethylating agents. These agents also showed similar growth-inhibitory effects in primary embryonic fibroblasts isolated from ko and wt mice. However, treatment with methyl methanesulfonate resulted in three- to fourfold more hprt mutations in splenic T lymphocytes from APNG ko mice than in those from wt mice. These mutations were predominantly single-base-pair changes; in the ko mice, they consisted primarily of AT-->TA and GC-->TA transversions, which most likely are caused by 3-meA and 3- or 7-meG, respectively. These results clearly show an important role for APNG in attenuating the mutagenic effects of N-alkylpurines in vivo.
CitationAlkylpurine-DNA-N-glycosylase knockout mice show increased susceptibility to induction of mutations by methyl methanesulfonate. 1998, 18 (10):5828-37 Mol. Cell. Biol.
JournalMolecular and Cellular Biology
- Modulation of the toxic and mutagenic effects induced by methyl methanesulfonate in Chinese hamster ovary cells by overexpression of the rat N-alkylpurine-DNA glycosylase.
- Authors: Calléja F, Jansen JG, Vrieling H, Laval F, van Zeeland AA
- Issue date: 1999 Apr 6
- Targeted deletion of alkylpurine-DNA-N-glycosylase in mice eliminates repair of 1,N6-ethenoadenine and hypoxanthine but not of 3,N4-ethenocytosine or 8-oxoguanine.
- Authors: Hang B, Singer B, Margison GP, Elder RH
- Issue date: 1997 Nov 25
- The effect of dietary folic acid deficiency on the cytotoxic and mutagenic responses to methyl methanesulfonate in wild-type and in 3-methyladenine DNA glycosylase-deficient Aag null mice.
- Authors: Branda RF, O'Neill JP, Brooks EM, Powden C, Naud SJ, Nicklas JA
- Issue date: 2007 Feb 3
- Tobacco BY-2 cells excise both 3-methyladenine and 7-methylguanine from methylated DNA.
- Authors: Kraszewska E, Dobrzańska M, Tudek B
- Issue date: 1998 Nov 12
- Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients.
- Authors: Agnihotri S, Gajadhar AS, Ternamian C, Gorlia T, Diefes KL, Mischel PS, Kelly J, McGown G, Thorncroft M, Carlson BL, Sarkaria JN, Margison GP, Aldape K, Hawkins C, Hegi M, Guha A
- Issue date: 2012 Jan