O-alkylation in DNA does not correlate with the formation of chromosome breakage events in D. melanogaster |
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| Authors: | E W Vogel |
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| Affiliation: | 1. Department of Physics, Tampere University of Technology, P. O. Box 692, FI-33101 Tampere, Finland;2. Department of Physics, University of Helsinki, P.O. Box 64, FI-00014 Helsinki, Finland;3. J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, v. v. i., Dolejskova 3, 18223 Prague 8, Czech Republic;4. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Prague 6, Czech Republic;5. MEMPHYS—Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark;1. Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada;2. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada;4. Brain and Cognition Discovery Foundation, Toronto, ON, Canada;5. Department of Psychological Medicine, Yong Loo Lin School of Medicine, National Universit of Singapore, Singapore;6. Institute for Health Innovaation and Technology (iHealthtech), National University of Singapore, Singapore;7. Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada;8. Centre for Addiction and Mental Health, Toronto, Ontario, Canada;1. GSI Environmental Inc, Austin, TX, United States;2. Independent Consultant, Canada;3. Department of Environmental Science, Stockholm University, 106 91, Stockholm, Sweden;4. Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, United States;5. School of Science and Technology, Örebro University, SE-701 82, Örebro, Sweden;6. New York University School of Medicine, United States;7. SciPinion, Bozeman, MT, United States;8. Lipscomb and Associates, Little Rock, AR, United States;9. Monash University, Australia;10. Rita Schoeny LLC, United States;11. Independent Consultant, United States;12. Universite de Montreal, Canada;1. GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom;2. Pfizer, Ramsgate Road Sandwich, Kent, CT13 9N, United Kingdom;3. AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NX, United Kingdom;4. Janssen R&D, Turnhoutseweg 30, 2340 Beerse, Belgium;1. Life and Health Sciences, Aston University, Birmingham B4 7ET, UK;2. Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, UK |
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| Abstract: | Postmeiotic cell stages of repair-proficient ring-X (RX) males were treated with methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), diethylnitrosamine (DEN) or ethylnitrosourea (ENU) and then mated to either repair-defective (mei-9L1) or to repair-competent females (mei-9+). Absence of the mei-9+ function resulted in a hypermutability effect to all alkylating agents (AAs) when they were assayed for their ability to induce chromosomal aberrations (chromosome loss; CL), irrespective of marked differences in distribution of DNA adducts brought about by these AAs. This picture is different from that described previously for the induction of point mutations (Vogel et al., 1985a). There, evidence was presented indicating that reduction in DNA excision repair does not affect point mutation induction (recessive lethals) by those AAs most efficient in ring-oxygen alkylation such as ENU, DEN, N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), and isopropyl methanesulfonate (iPMS): the order of hypermutability of AAs with mei-9L relative to mei-9+ was MMS greater than MNU greater than DMN = EMS greater than iPMS = ENU = DEN = ENNG. When the percentage of lethal mutations induced in mei-9L1 females were plotted against those determined for mei-9+ females, straight lines of following slopes were obtained: MMS = 7.6, MNU = 5.4, DMN = 2.4, EMS = 2.4, and iPMS = ENU = DEN = ENNG = 1. Those findings, together with the recent observation that AAs do not split into two groups when assayed for their ability to cause CL, point to the involvement of different DNA alkylation products in ENU- and DEN-induced chromosome loss vs. that of point mutations. It is concluded that with ENU and DEN chromosomal loss results from N-alkylation products whereas point mutations (SLRL) are the consequence of interactions with oxygen-sites in DNA. Thus, as a consequence of a very dominating role of O-ethylguanine (and possibly O4-alkylation of thymine), N-alkylation in DNA does not contribute measurably to mutation induction in the case of ENU-type mutagens while O-alkylation, very clearly, does not show a positive correlation with the formation of chromosome breakage events in Drosophila. Conversely, it appeared that with MMS-type mutagens (MMS; dimethyl sulfate, DMS; trimethyl phosphate, TMP), alkylation products such as 7-methylguanine and 3-methyladenine, if unrepaired or misrepaired, are potentially mutagenic lesions causing both mutations and chromosomal aberrations. |
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