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

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 doublestrand 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.

DNA Damage-Induced Phosphorylation of TRF2 Is Required for the Fast Pathway of DNA Double-Strand Break Repair

“…The median numbers of foci/nucleus are shown numerically and as red dots. (3,28), along with results from others showing that TRF2 performs roles in the DNA damage response (17,19,20,22,30), strongly suggest that TRF2 functions at DNA DSBs and that DNA damage-induced phosphorylation of TRF2 may facilitate its localization to these damage sites. Additionally, DNA damage-induced phosphorylation of TRF2 may function to allow TRF2 to perform a direct role as a mediator or effector in the DNA damage response.…”

“…These reports suggest that TRF2 (i) is required for the repair of DBS breaks via the homologous recombination pathway (17), (ii) interacts at nontelomeric sites physically and genetically with several proteins known to function in various pathways of DNA repair (19,20), (iii) plays an important role in drug resistance (22,30), and (iv) migrates to DNA damage sites (3,28). One report repeated previous results regarding TRF2 migration to DNA damage sites using the same damage source as used by Bradshaw et al (3) but did not observe TRF2 at damage sites using another damage source (29).…”

C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment

“…Mice genetically deficient in CXCR7 have abnormalities in their cardiovascular and central nervous systems [12]. CXCR7 expression in NSCL and breast cancer is correlated with lymph node metastasis and poor prognosis [66,67]. …”

One Identity or More for Telomeres?

“…In unicellular eukaryotes, topoisomerase 2 was shown to play a role in telomeres segregation in the fission yeast (Germe et al, 2009). In human cells, the telomeric G4-targeting molecule RHPS4 potentiates the anti-tumor efficacy of TOPO I (topoisomerase I) inhibitors in preclinical models (Leonetti et al, 2008; Biroccio et al, 2011) and TRF2 protects against the damages caused by topoisomerase 2 poisons (Klapper et al, 2003; Zhang et al, 2008). Furthermore, topoisomerase 2α is required for telomere protection in a pathway involving TRF2 and its partner Apollo (Ye et al, 2010).…”