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Research ArticleArticle

The Telomeric Protein TRF2 Is Critical for the Protection of A549 Cells from Both Telomere Erosion and DNA Double-Strand Breaks Driven by Salvicine

Yong-Wei Zhang, Zhi-Xiang Zhang, Ze-Hong Miao and Jian Ding
Molecular Pharmacology March 2008, 73 (3) 824-832; DOI: https://doi.org/10.1124/mol.107.039081
Yong-Wei Zhang
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Zhi-Xiang Zhang
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Ze-Hong Miao
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Jian Ding
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This article has a correction. Please see:

  • Correction to “The Telomeric Protein TRF2 Is Critical for the Protection of A549 Cells from Both Telomere Erosion and DNA Double-Strand Breaks Driven by Salvicine” - May 01, 2008

Abstract

Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in DNA damage response and telomere maintenance. Our previous report found that salvicine (SAL), a novel topoisomerase II poison, elicited DNA double-strand breaks and telomere erosion in separate experimental systems. However, it remains to be clarified whether they share a common response to these two events and in particular whether TRF2 is involved in this process. In this study, we found that SAL concurrently induced DNA double-strand breaks, telomeric DNA damage, and telomere erosion in lung carcinoma A549 cells. It was unexpected to find that SAL led to disruption of TRF2, independently of either its transcription or proteasome-mediated degradation. By overexpressing the full-length trf2 gene and transfecting TRF2 small interfering RNAs, we showed that TRF2 protein protected both telomeric and genomic DNA from the SAL-elicited events. It is noteworthy that although both the Ataxia-telangiectasia-mutated (ATM) and the ATM- and Rad3-related (ATR) kinases responded to the SAL-induced DNA damages, only ATR was essential for the telomere erosion. The study also showed that the activated ATR augmented the SAL-triggered TRF2 disruption, whereas TRF2 reduction in turn enhanced ATR function. All of these findings suggest the emerging significance of TRF2 protecting both telomeric DNA and genomic DNA on the one hand and reveal the mutual modulation between ATR and TRF2 in sensing DNA damage signaling during cancer development on the other hand.

Footnotes

  • This work was supported by the grants from the National Natural Sciences Foundation of China (30500618 and 30721005) and the Chinese Academy of Sciences (the special scientific research initiation fund for Z.-H.M., the winner of the Special Prize of the President Scholarship).

  • ABBREVIATIONS: TRF2, telomere repeat binding factor 2; SAL, salvicine; ATM, ataxia-telangiectasia-mutated; ATR, ataxia-telangiectasia-mutated- and Rad3-related; DSB, double-strand break; ChIP, chromatin immunoprecipitation; siRNA, small interfering RNA; ppt, protein-DNA immunoprecipitate complex; PCR, polymerase chain reaction; RT-PCR, reverse-transcription polymerase chain reaction; MG-132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; DMSO, dimethyl sulfoxide; FITC, fluorescein isothiocyanate; PBS, phosphate-buffered saline; DAPI, 4,6-diamidino-2-phenylindole; VP16, etopside; γ-H2AX, phosphorylated-H2AX; A, absorbance.

    • Received June 15, 2007.
    • Accepted November 19, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (3)
Molecular Pharmacology
Vol. 73, Issue 3
1 Mar 2008
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Research ArticleArticle

The Telomeric Protein TRF2 Is Critical for the Protection of A549 Cells from Both Telomere Erosion and DNA Double-Strand Breaks Driven by Salvicine

Yong-Wei Zhang, Zhi-Xiang Zhang, Ze-Hong Miao and Jian Ding
Molecular Pharmacology March 1, 2008, 73 (3) 824-832; DOI: https://doi.org/10.1124/mol.107.039081

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Research ArticleArticle

The Telomeric Protein TRF2 Is Critical for the Protection of A549 Cells from Both Telomere Erosion and DNA Double-Strand Breaks Driven by Salvicine

Yong-Wei Zhang, Zhi-Xiang Zhang, Ze-Hong Miao and Jian Ding
Molecular Pharmacology March 1, 2008, 73 (3) 824-832; DOI: https://doi.org/10.1124/mol.107.039081
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