A G-quadruplex stabilizer induces M-phase cell cycle arrest

Yuan Chin Tsai, Haiyan Qi, Chao P. Lin, Ren K. Lin, John E. Kerrigan, Suzanne G. Rzuczek, Edmond J. LaVoie, Joseph E. Rice, Daniel S. Pilch, Yi Lisa Lyu, Leroy F. Liu

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

G-quadruplex stabilizers such as telomestatin and HXDV bind with exquisite specificity to G-quadruplexes, but not to triplex, duplex, or single-stranded DNAs. Studies have suggested that the antiproliferative and possibly anti-tumor activities of these compounds are linked to their inhibitory effect on telomerase and/or telomere function. In the current studies, we show that HXDV, a synthetic analog of telomestatin, exhibits antiproliferative activity against both telomerase-positive and -negative cells and induces robust apoptosis within 16 h of treatment, suggesting a mode of action independent of telomerase. HXDV was also shown to inhibit cell cycle progression causing M-phase cell cycle arrest, as evidenced by accumulation of cells with 4 N DNA content, increased mitotic index, separated centrosomes, elevated histone H3 phosphorylation at Ser-10 (an M-phase marker), and defective chromosome alignment and spindle fiber assembly (revealed by time-lapse microscopy). The M-phase arrest caused by HXDV paralleled with reduction in the expression level of the major M-phase checkpoint regulator Aurora A. All these cellular effects appear to depend on the G-quadruplex binding activity of HXDV as its non-G-quadruplex binding analog, TXTLeu, is completely devoid of all these effects. In the aggregate, our results suggest that HXDV, which exhibits anti-proliferative and apoptotic activities, is also a novel M-phase blocker, with a mode of action dependent on its G-quadruplex binding activity.

Original languageEnglish
Pages (from-to)22535-22543
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number34
DOIs
Publication statusPublished - Aug 21 2009
Externally publishedYes

Fingerprint

G-Quadruplexes
M Phase Cell Cycle Checkpoints
Telomerase
Cells
Cell Division
Phosphorylation
Single-Stranded DNA
Chromosomes
Histones
Centrosome
Mitotic Index
Tumors
Telomere
Microscopic examination
Genetic Markers
Apoptosis
Microscopy
Cell Cycle
Fibers
DNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

A G-quadruplex stabilizer induces M-phase cell cycle arrest. / Tsai, Yuan Chin; Qi, Haiyan; Lin, Chao P.; Lin, Ren K.; Kerrigan, John E.; Rzuczek, Suzanne G.; LaVoie, Edmond J.; Rice, Joseph E.; Pilch, Daniel S.; Lyu, Yi Lisa; Liu, Leroy F.

In: Journal of Biological Chemistry, Vol. 284, No. 34, 21.08.2009, p. 22535-22543.

Research output: Contribution to journalArticle

Tsai, YC, Qi, H, Lin, CP, Lin, RK, Kerrigan, JE, Rzuczek, SG, LaVoie, EJ, Rice, JE, Pilch, DS, Lyu, YL & Liu, LF 2009, 'A G-quadruplex stabilizer induces M-phase cell cycle arrest', Journal of Biological Chemistry, vol. 284, no. 34, pp. 22535-22543. https://doi.org/10.1074/jbc.M109.020230
Tsai YC, Qi H, Lin CP, Lin RK, Kerrigan JE, Rzuczek SG et al. A G-quadruplex stabilizer induces M-phase cell cycle arrest. Journal of Biological Chemistry. 2009 Aug 21;284(34):22535-22543. https://doi.org/10.1074/jbc.M109.020230
Tsai, Yuan Chin ; Qi, Haiyan ; Lin, Chao P. ; Lin, Ren K. ; Kerrigan, John E. ; Rzuczek, Suzanne G. ; LaVoie, Edmond J. ; Rice, Joseph E. ; Pilch, Daniel S. ; Lyu, Yi Lisa ; Liu, Leroy F. / A G-quadruplex stabilizer induces M-phase cell cycle arrest. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 34. pp. 22535-22543.
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