Johnson, Kaitlin and Seidel, Julia M. and Cech, Thomas R. (2024) Small molecule telomerase inhibitors are also potent inhibitors of telomeric C-strand synthesis. RNA, 30 (9). pp. 1213-1226. ISSN 1355-8382, 1469-9001
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Telomere replication is essential for continued proliferation of human cells, such as stem cells and cancer cells. Telomerase lengthens the telomeric G-strand, while C-strand replication is accomplished by CST-polymerase alpha-primase (CST-PP). Replication of both strands is inhibited by formation of G-quadruplex (GQ) structures in the G-rich single-stranded DNA. TMPyP4 and pyridostatin (PDS), which stabilize GQ structures in both DNA and RNA, inhibit telomerase in vitro, and in human cells they cause telomere shortening that has been attributed to telomerase inhibition. Here, we show that TMPyP4 and PDS also inhibit C-strand synthesis by stabilizing DNA secondary structures and thereby preventing CST-PP from binding to telomeric DNA. We also show that these small molecules inhibit CST-PP binding to a DNA sequence containing no consecutive guanine residues, which is unlikely to form GQs. Thus, while these "telomerase inhibitors" indeed inhibit telomerase, they are also robust inhibitors of telomeric C-strand synthesis. Furthermore, given their binding to GQ RNA and their limited specificity for GQ structures, they may disrupt many other protein-nucleic acid interactions in human cells.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DNA-POLYMERASE ALPHA; HUMAN CST; CIRCULAR-DICHROISM; DUPLEX REPLICATION; BINDING; RNA; COMPLEX; SELECTIVITY; TMPYP4; G-quadruplex; GQ stabilizers; pyridostatin; TMPyP4; telomere replication |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Biochemie III |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Jan 2026 06:24 |
| Last Modified: | 15 Jan 2026 06:24 |
| URI: | https://pred.uni-regensburg.de/id/eprint/64925 |
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