Inhibition of Human Telomerase Activity by an Engineered Zinc Finger Protein That Binds G-quadruplexes

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2004 Oct 20

PMID 15491152

Citations 16

Authors

Sachin D Patel

Mark Isalan

Gerald Gavory

Sylvain Ladame

Yen Choo

Shankar Balasubramanian

Affiliations

Soon will be listed here.

Abstract

The G-quadruplex nucleic acid structural motif is a target for designing molecules that could potentially modulate telomere length or have anticancer properties. We have recently described an engineered zinc finger protein (Gq1) that binds with specificity to the intramolecular G-quadruplex formed by the human telomeric sequence 5'-(GGTTAG)(5)-3' (Isalan et al. (2001) Biochemistry 40, 830-836). Here, we report that Gq1 is able to arrest the action of a DNA polymerase on a template-containing telomeric sequence. Inhibition occurs in a concentration-dependent manner, probably by forming a stabilized G-quadruplex.protein complex. Furthermore, Gq1 inhibits the apparent activity of the enzyme telomerase in vitro, with an IC(50) value of 74.3 +/- 11.1 nM. Possible molecular mechanisms of inhibition are discussed, together with the potential for using engineered zinc fingers to interfere with the cellular processes associated with telomere function.

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