DNA adducts of antitumor cisplatin preclude telomeric sequences from forming G quadruplexes.
We studied the effect of antitumor cisplatin and inefficient transplatin on the structure and stability of G quadruplexes formed by the model human telomere sequence 5'-GGG(TTAGGG)(3)-3' using circular dichroism, UV-monitored thermal denaturation, and gel electrophoresis. In addition, to investigate whether there is a connection between the ability of cisplatin or transplatin to affect telomerase activity and stability of G quadruplexes, we also used a modified telomere repeat amplification protocol assay that uses an oligonucleotide substrate for telomerase elongation susceptible to forming a G quadruplex. The results indicate that cisplatin is more efficient than transplatin in disturbing the quadruplex structure, thereby precluding telomeric sequences from forming quadruplexes. On the other hand, the results of this work also demonstrate that in absence of free platinum complex, DNA adducts of antitumor cisplatin inhibit telomerase catalysis, so the mechanism underlying this inhibition does not involve formation of the G quadruplexes which are not elongated by telomerase.
Heringova
Pavla
P
Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
Kasparkova
Jana
J
Brabec
Viktor
V
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D055162:Biocatalysis; D002942:Circular Dichroism; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology*; D018736:DNA Adducts / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D021141:Nucleic Acid Amplification Techniques; D009691:Nucleic Acid Denaturation; D013056:Spectrophotometry, Ultraviolet; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000235:genetics*; D044366:Transition Temperature
D000970:Antineoplastic Agents; D018736:DNA Adducts; C034697:transplatin; D019098:Telomerase; D002945:Cisplatin