Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents

http://nar.oxfordjournals.org/content/early/2015/10/19/nar.gkv1061.full

Wei-Chun Huang, Ting-Yuan Tseng, Ying-Ting Chen, Cheng-Chung Chang, Zi-Fu Wang, Chiung-Lin Wang, Tsu-Ning Hsu, Pei-Tzu Li, Chin-Tin Chen, Jing-Jer Lin, Pei-Jen Lou and Ta-Chau Chang

When DNA has a high content of guanine (one of the bases of DNA), under certain conditions, it can form a more exotic structure than the well-known Watson-Crick base pairing, known as a G-quadruplex. This is where four guanine bases bond to form a square-planar structure. These planes can stack on top of each other, to form the G-quadruplex. These structures can form in vivo, and are thought to have a connection to telomeres.

In this paper, the authors explore the existence of G4-quadruplexes in mtDNA. They do this by using fluorescent compounds which are able to both bind to a G4-quadruplex, and also localise in mitochondria (rather than the cell nucleus). One such agent is called BMVC-12C-P. What is curious about this particular agent is that it is able to halt the proliferation of cells in a cancer-specific manner. The agent accumulates strongly in the mitochondria of HeLa cancer cells, whereas it mainly localises in the lysosome of MRC-5 normal fibroblasts. The anti-cancer effect of this agent is robust across 3 cancer cell lines, and 3 normal cell lines, that were tested. Tumour proliferation was also shown to be slowed in mice injected with cancer cells, and treated with BMVC-12C-P.

After 72 hours of treatment, the authors find that the expression of ND3 and COX1 transcripts were severely reduced. Thus, the authors suggest that the mechanism of cytotoxicity of this agent is to prevent mtDNA transcription of these core ETC components, by targeting G4-quadruplexes in mtDNA. As well as being an interesting agent in its own right, this study provides further evidence for mtDNA being a target to alter cell proliferation.