More pronounced salt dependence and higher reactivity for platination of the hairpin r(CGCGUUGUUCGCG) compared with d(CGCGTTGTTCGCG)

Hägerlöf, Margareta; Papsai, Pal; Chow, Christine S.; Elmroth, Sofi K. C.

doi:10.1007/s00775-006-0157-y

Cited by 33 publications

(34 citation statements)

References 85 publications

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“…The application of polyelectrolyte theory to the platination of RNA or DNA suggests a model involving entry of a charged platinum species into the condensed cation atmosphere of a nucleic acid, followed by irreversible monoadduct and diadduct formation 12,58–60. The range of literature values for the rate of monoadduct formation on duplex DNA by [Pt(NH 3 ) 2 Cl(OH 2 )] + varies from ~0.1 to 1 M −1 s −1 61–63.…”

Section: Discussionmentioning

confidence: 99%

Rapid Cross-Linking of an RNA Internal Loop by the Anticancer Drug Cisplatin

2009

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Cisplatin is the most prominent member of a series of platinum(II) antitumor drugs that demonstrate activity based on binding to adjacent purines on genomic DNA. The interactions between cisplatin and alternate biomolecules, including chemically similar RNA, are less understood than are those for DNA. In order to investigate potential implications of platinum(II) drug binding to a structurally complex RNA, we have characterized the reaction between cisplatin and the internal loop of a 41-nucleotide subdomain derived from the U2:U6 spliceosomal RNAs. This "BBD" RNA subdomain consists of a hairpin structure containing a purine-rich asymmetric internal loop. Aquated cisplatin is found to cross-link G nucleobases on opposing sides of the internal loop, forming an intramolecular internal loop cross-link in BBD and an analogous intermolecular cross-link in a two-piece construct containing the same internal loop sequence. The two opposing guanine residues involved in the crosslink were identified via limited alkaline hydrolysis. The kinetics of aquated cisplatin binding to the BBD RNA, a related RNA hairpin, and its DNA hairpin analogue were investigated in an ionic background of 0.1 M NaNO 3 and 1 mM Mg(NO 3 ) 2 . Both BBD and the RNA hairpin react 5-6-fold faster than the DNA hairpin, with calculated second-order rate constants of 2.0(2), 1.7(3), and 0.33 (3) M −1 s −1 , respectively, at 37 °C, pH 7.8. MALDI-MS data corroborate the biochemical studies and support a model in which kinetically preferred platinum binding sites compete with less reactive sites in these oligonucleotides. Taken together, these data indicate that cisplatin treatment has potential to create internal loop and other unusual cross-links in structurally complex RNAs, on a time scale that is relevant for RNA-dependent biological processes.

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Section: Discussionmentioning

confidence: 99%

Rapid Cross-Linking of an RNA Internal Loop by the Anticancer Drug Cisplatin

2009

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“…These results are complemented by in vitro studies describing RNA oligonucleotide targeting by cisplatin 13–18 and by several Pt-drug conjugates. 19,20 In addition to these studies, our lab has recently reported that cisplatin is capable of crosslinking structurally complex RNAs.…”

Section: Introductionmentioning

confidence: 95%

“…19,20 In addition to these studies, our lab has recently reported that cisplatin is capable of crosslinking structurally complex RNAs. 21 Elmroth and coworkers 18 and our laboratory 21 have reported that in vitro , RNA binding is kinetically preferred over drug coordination to DNA. Taken together these initial findings raise important questions regarding which types of cellular RNAs may be targeted by cisplatin, and whether cellular RNA function is significantly impaired as a result.…”

Section: Introductionmentioning

confidence: 99%

Enzymatic Processing of Platinated RNAs

Chapman

DeRose

2010

J. Am. Chem. Soc.

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The broadly prescribed anti-tumor 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 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 anti-tumor 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.

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“…This finding suggests that short RNAs may also represent good targets for cisplatin [77,78], and prompted further studies to better elucidate the basis of platinum-RNA interaction. Interestingly, in vitro studies performed using mono-aquated platinum complexes have shown that RNA platination kinetically competes or is even preferred over DNA platination [80,93]. Elmroth and co-workers investigated the interaction of cisplatin with the full length tRNA Ala and a short hairpin model (Mh Ala ) of its GC rich acceptor stem region ( Fig.…”

Section: Platinum Binding To Rnamentioning

confidence: 98%

Covalent and non-covalent binding of metal complexes to RNA

Alberti

Zampakou

Donghi

2016

Journal of Inorganic Biochemistry

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Targeting nucleic acids with metal complexes is an exciting and widely explored field of research. Following the discovery of the anticancer drug cisplatin, a number of metal complexes have been designed, synthesised, and tested for their DNA binding properties. On the contrary, the interaction of metal complexes with RNA has been much less investigated. RNA is an essential biomolecule, involved in a variety of crucial cellular functions, which offers a much wider structural diversity than DNA. As such, RNA represents an attractive target for the design and the development of structure-selective therapeutic and diagnostic agents. A few recent publications describe the ability of various metal complexes to interact with RNA, and the binding of cisplatin and derivatives to RNA is being currently investigated. This short review offers an overview of some recent advances on both covalent and non-covalent interactions of metal complexes with RNA and addresses the potential of targeting RNA non-duplex structures.

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More pronounced salt dependence and higher reactivity for platination of the hairpin r(CGCGUUGUUCGCG) compared with d(CGCGTTGTTCGCG)

Cited by 33 publications

References 85 publications

Rapid Cross-Linking of an RNA Internal Loop by the Anticancer Drug Cisplatin

Rapid Cross-Linking of an RNA Internal Loop by the Anticancer Drug Cisplatin

Enzymatic Processing of Platinated RNAs

Covalent and non-covalent binding of metal complexes to RNA

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