Arsenite enhances DNA double-strand breaks and cell killing of methyl methanesulfonate-treated cells by inhibiting the excision of alkali-labile sites.
Analysis of DNA strand breaks by alkaline elution indicates that DNA repair of Chinese hamster ovary cells treated with methyl methanesulfonate (MMS) was inhibited by sodium arsenite. Comparing the profiles of a 36-min elution with buffer pH 12.1 and a 12-h elution with buffer pH 12.4 revealed that alkali-labile sites were increased more than frank breaks in the combined treatment with MMS plus arsenite. Enhancement of alkali-labile sites was detected with low doses of MMS and arsenite, whereas enhancement of frank breaks required higher doses of MMS and arsenite. Double-strand breaks were detected after incubating the MMS-treated cells in an arsenite-containing medium for 18 or 12 h but not less than 6 h. No double-strand breaks were detected when MMS-damaged cells were posttreated with arsenite for 3 h; however, double-strand breaks were detected after further incubating these cells in arsenite-free medium for 18 h. Thus, inhibition of arsenite on the excision of methylated bases may have accumulated a large number of alkali-labile sites in the parental strands, and DNA replication may then generate breaks in the non-methylated daughter strands. Double-strand breaks may result from overlapping gaps between the parental and daughter strands and/or postreplication repair. These double-strand breaks may then result in the synergistic cell death as observed with posttreatment of MMS-damaged cells with arsenite for 1 or 3 h.
Lee-Chen
S F
SF
Institute of Zoology, Academia Sinica, Taipei, Taiwan, ROC.
Gurr
J R
JR
Lin
I B
IB
Jan
K Y
KY
D000477:Alkylating Agents / Q000378:metabolism; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D018053:Arsenites; D001665:Binding Sites / Q000187:drug effects; D016466:CHO Cells; D016923:Cell Death; D006224:Cricetinae; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008741:Methyl Methanesulfonate / Q000633:toxicity*; D008745:Methylation; D016296:Mutagenesis; D017670:Sodium Compounds
D000477:Alkylating Agents; D018053:Arsenites; D017670:Sodium Compounds; C017947:sodium arsenite; D004247:DNA; D008741:Methyl Methanesulfonate; D001151:Arsenic