Designer enediynes generate DNA breaks, interstrand cross-links, or both, with concomitant changes in the regulation of DNA damage responses.
The ability of the radiomimetic anticancer enediyne C-1027 to induce ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR)-independent damage responses was discovered to reside in its unique ability to concurrently generate robust amounts of double-strand breaks (DSBs) and interstrand cross-links (ICLs) in cellular DNA. Furthermore, a single substitution to the chromophore's benzoxazolinate moiety shifted DNA damage to primarily ICLs and an ATR- but not ATM-dependent damage response. In contrast, single substitutions of the chromophore's beta-amino acid component shifted DNA damage to primarily DSBs, consistent with its induction of conventional ATM-dependent damage responses of the type generated by ionizing radiation and other radiomimetics. Thus, phosphatidylinositol 3-kinase-like protein kinase regulation of DNA damage responses is dictated by the relative proportions of DSBs and ICLs.
Kennedy
Daniel R
DR
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Ju
Jianhua
J
Shen
Ben
B
Beerman
Terry A
TA
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001260:Ataxia Telangiectasia / Q000235:genetics; D003432:Cross-Linking Reagents / Q000138:chemical synthesis*; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004279:DNA, Viral / Q000235:genetics; D053281:Enediynes / Q000138:chemical synthesis / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D009154:Mutation; D009690:Nucleic Acid Conformation; D010957:Plasmids; D013539:Simian virus 40 / Q000235:genetics
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004279:DNA, Viral; D053281:Enediynes; D004247:DNA