Small molecule telomerase inhibitors are also potent inhibitors of telomeric C-strand synthesis. Journal Article uri icon

Overview

abstract

  • 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 α-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.

publication date

  • August 16, 2024

has subject area

has restriction

  • bronze

Date in CU Experts

  • June 26, 2024 3:46 AM

Full Author List

  • Johnson K; Seidel JM; Cech TR

author count

  • 3

published in

  • RNA  Journal

Other Profiles

Electronic International Standard Serial Number (EISSN)

  • 1469-9001

Additional Document Info

start page

  • 1213

end page

  • 1226

volume

  • 30

issue

  • 9