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Mechanisms of RNA polymerase II processing of DNA lesions formed by novel monofunctional platinum anticancer drugs (560.11)
Author(s) -
Wang Dong
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.560.11
Subject(s) - cisplatin , carboplatin , chemistry , dna , mechanism of action , polymerase , dna damage , rna polymerase ii , transcription (linguistics) , adduct , stereochemistry , biochemistry , biology , gene , gene expression , genetics , in vitro , promoter , linguistics , philosophy , organic chemistry , chemotherapy
Pyriplatin and Phenanthriplatin, a novel class of platinum compounds, forms monofunctional DNA lesions having a structure and spectrum of anticancer activity distinct from those of the FDA‐approved drugs cisplatin, carboplatin, and oxaliplatin. These novel structure‐activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site‐specific monofunctional pyriplatin‐DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV‐induced 1,2‐intrastrand cross‐links. In addition, we present the systematic mechanistic investigation that addresses how a site‐specific platinum‐DNA monofunctional adduct affects the Pol II elongation and transcriptional fidelity checkpoint steps, which is an important step toward elucidating the mechanism of action of these compounds. Our findings provide insight into structure‐activity relationships that may apply to the entire family of monofunctional DNA‐damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs.