Nucleic Acids Research, Vol 25, Issue 15 3074-3081, Copyright © 1997 by Oxford University Press
T Kuwabara, M Warashina, T Tanabe, K Tani, S Asano and K Taira
With the eventual goal of developing a treatment for chronic myelogenous
leukemia (CML), attempts have been made to design hammerhead ribozymes that
can specifically cleave BCR-ABL fusion mRNA. In the case of L6 BCR-ABL
fusion mRNA (b2a2 type; BCR exon 2 is fused to ABL exon 2), which has no
effective cleavage sites for conventional hammerhead ribozymes near the
BCR-ABL junction, it has proved very difficult to cleave the chimeric mRNA
specifically. Several hammerhead ribozymes with relatively long
junction-recognition sequences have poor substrate-specificity. Therefore,
we explored the possibility of using newly selected DNA enzymes that can
cleave RNA molecules with high activity to cleave L6 BCR-ABL fusion (b2a2)
mRNA. In contrast to the results with the conventional ribozymes, the newly
designed DNA enzymes, having higher flexibility for selection of cleavage
sites, were able to cleave this chimeric RNA molecule specifically at sites
close to the junction. Cleavage occurred only within the abnormal BCR- ABL
mRNA, without any cleavage of the normal ABL or BCR mRNA. Thus, these
chemically synthesized DNA enzymes seem to be potentially useful for
application in vivo , especially for the treatment of CML, if we can
develop exogenous delivery strategies.
ARTICLES
Comparison of the specificities and catalytic activities of hammerhead ribozymes and DNA enzymes with respect to the cleavage of BCR-ABL chimeric L6 (b2a2) mRNA
National Institute for Advanced Interdisciplinary Research, 1-1 Higashi, Tsukuba Science City 305, Japan.
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