Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Kennedy DR,Ju J,Shen B,Beerman TAdoi
10.1073/pnas.0708274104subject
Has Abstractpub_date
2007-11-06 00:00:00pages
17632-7issue
45eissn
0027-8424issn
1091-6490pii
0708274104journal_volume
104pub_type
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