Book of Abstracts: Albany 2007

category image Albany 2007
Conversation 15
June 19-23 2007

Cisplatin-RNA adducts: Crosslinking of a spliceosomal RNA subdomain by an anticancer compound

The highly effective anticancer drug cisplatin [Pt(NH3)2Cl2] and its aquated derivatives form Pt(II) adducts with nucleic acids predominantly at purine N7 positions. The major adducts investigated involve intrastrand coordination to 5?G-G and 5?A-G sites in DNA duplexes. These kinetically stable adducts result in downstream effects including signaling of apoptotic pathways, causing cell death. (1)

Very little is known about cisplatin adducts with more complex nucleic acid structures, including the varied secondary and tertiary motifs found in functional RNAs. Recent studies have demonstrated formation of unique RNA-cisplatin complexes (2). Naturally-occurring metal sites in RNA often consist of ligands that are far apart in primary sequence and brought into proximity in the folded form. (3) Non-labile Pt(II) adducts between these sites may have significant effects on the biological activity of RNA, which can involve dynamic folding and unfolding events.

This poster will present recent advances in characterizing the nature of platinum adducts formed in an RNA subdomain derived from the U2/U6 snRNA complex. Previous studies from this lab strongly suggest that platination results in formation of an interstrand crosslink across an internal loop of this subdomain. Chemical and RNase mapping are being employed in order to identify specific bases involved in this crosslinking adduct. Kinetic studies of adduct formation, including the influence of ionic conditions, will be presented.

References and Footnotes
  1. Wang, D., Lippard, S. J. Nature Reviews Drug Discovery 4, 307-320 (2005).
  2. Hagerlof, M.; Papsai, P.; Chow, C. S.; Elmroth, S. K. C. Journal of Biological Inorganic Chemistry 11, 974-990 (2006).
  3. DeRose, V.J., Burns, S., Vogt, M., Kim, N.-K. "RNA and DNA as Ligands" Comprehensive Coordination Chemistry II J.A. McCleverty, T.J. Meyers, Eds., Elsevier, Oxford, pp. 787-813 (2003).

Victoria J. DeRose
Alethia Hostetter, and
Erich Chapman

Department of Chemistry,
University of Oregon,
Eugene, OR 97403-1253

Tel: 541-346-3568
Email: derose@uoregon.edu