期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 35, 页码 12311-12316出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0506025102
关键词
cancer; carboplatin; chromatin; DNA repair; DNA structure
资金
- NCI NIH HHS [R01 CA034992, R37 CA034992, CA-34992] Funding Source: Medline
- NIGMS NIH HHS [R01 GM041930, GM41930] Funding Source: Medline
We constructed two site-specifically modified nucleosomes containing an intrastrand cis-[Pt(NH3)(2)}(2+) 1,3-d(GpTpG) cross-link, similar to one formed by the anticancer drugs carboplatin and cisplatin on DNA, and investigated their structures by hydroxyl radical footprinting and exonuclease III digestion. Hydroxyl radical footprinting demonstrated that the presence of the platinum cross-link selects out a specific rotational setting of DNA on the histone octamer core in each of two reconstituted nucleosomes in which the platinum positions differ by half a DNA helical turn. The (Pt(NH3)2)2+ cross-link is situated in a structurally similar location, with the undamaged strand projecting outward, forcing the DNA to adopt opposite rotational settings in its wrapping around the histone octamer in the two nucleosomes. Enzymatic digestion by exonuclease III of the nucleosome substrates revealed that the platinum cross-link affects the translational positioning of the DNA, forcing it into an asymmetric arrangement with respect to the core histone proteins. We suggest that these phasing phenomena may be central to the recognition and processing of platinum-DNA adducts in cancer cells treated with these drugs and possibly may be common to other DNA damaging events.
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