Enzymatic Processing of Platinated RNAs
- 25 January 2010
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 132 (6), 1946-1952
- https://doi.org/10.1021/ja908419j
Abstract
The broadly prescribed antitumor drug cisplatin coordinates to DNA, altering the activity of cellular proteins whose functions rely upon sensing DNA structure. Cisplatin is also known to coordinate to RNA, but the effects of RNA−Pt adducts on the large number of proteins that process the transcriptome are currently unknown. In an effort to address how platination of an RNA alters the function of RNA processing enzymes, we have determined the influence of [Pt(NH3)2]2+−RNA adducts on the activities of 3′→5′ and 5′→3′ phosphodiesterases, a purine-specific endoribonuclease, and a reverse transcriptase. Single Pt(II) adducts on RNA oligonucleotides of the form (5′-U6-XY-U5-3′: XY = GG, GA, AG, GU) are found to block exonucleolytic digestion. Similar disruption of endonucleolytic cleavage is observed, except for the platinated XY = GA RNA where RNase U2 uniquely tolerates platinum modification. Platinum adducts formed with a more complex RNA prevent reverse transcription, providing evidence that platination is capable of interfering with RNA’s role in relaying sequence information. The observed disruptions in enzymatic activity point to the possibility that cellular RNA processing may be similarly affected, which could contribute to the cell-wide effects of platinum antitumor drugs. Additionally, we show that thiourea reverses cisplatin−RNA adducts, providing a chemical tool for use in future studies regarding cisplatin targeting of cellular RNAs.Keywords
This publication has 65 references indexed in Scilit:
- Rapid Cross-Linking of an RNA Internal Loop by the Anticancer Drug CisplatinJournal of the American Chemical Society, 2009
- The Many Pathways of RNA DegradationCell, 2009
- Phosphodiester-Mediated Reaction of Cisplatin with Guanine in OligodeoxyribonucleotidesBiochemistry, 2008
- Protein factors in pre-mRNA 3′-end processingCellular and Molecular Life Sciences, 2007
- Kinetically Favored Platination of Adenine in the G-Rich Human Telomeric RepeatJournal of the American Chemical Society, 2007
- Cisplatin Damage Overrides the Predefined Rotational Setting of Positioned NucleosomesJournal of the American Chemical Society, 2007
- Bifunctional Binding of Cisplatin to DNA: Why Does Cisplatin Form 1,2-Intrastrand Cross-Links with AG But Not with GA?Journal of the American Chemical Society, 2007
- Cellular processing of platinum anticancer drugsNature Reviews Drug Discovery, 2005
- Ribonuclease T1: Structure, Function, and StabilityAngewandte Chemie, 1991
- Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: formation, identification, and quantitationBiochemistry, 1985