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First published on November 19, 2007; DOI: 10.1124/mol.107.039081

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Received for publication June 15, 2007.
Revised November 19, 2007.
Accepted for publication November 19, 2007.

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 1, Zhi-Xiang Zhang 1, Ze-Hong Miao 1, Jian Ding 1*

1 Shanghai Institute of Materia Medica

* Address correspondence to: E-mail: jding{at}mail.shcnc.ac.cn

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 and if TRF2 involves 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. Unexpectedly, SAL led to disruption of TRF2, independently of either its transcription or proteasome-mediated degradation. By over-expressing 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. Notably, though 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 while TRF2 reduction in turn enhanced ATR function. All these findings suggest the emerging significance of TRF2 protecting both telomeric DNA and genomic DNA on one hand, and reveal the mutual modulation between ATR and TRF2 in sensing DNA damage signaling during cancer development on the other hand.


Key words: DNA damage and repair, Topoisomerases


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N. Huda, H. Tanaka, M. S. Mendonca, and D. Gilley
DNA Damage-Induced Phosphorylation of TRF2 Is Required for the Fast Pathway of DNA Double-Strand Break Repair
Mol. Cell. Biol., July 1, 2009; 29(13): 3597 - 3604.
[Abstract] [Full Text] [PDF]


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