期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 45, 页码 17632-17637出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0708274104
关键词
DNA double-strand break; C-1027; radioimetic; ATM; ATR
资金
- NCI NIH HHS [T32 CA009072, R01 CA106312, U19 CA113297, CA113297, CA106312, CA09072-30, P30 CA016056, R01 CA078747, CA078747, CA16056] Funding Source: Medline
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 p-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.
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