A Curious DNA Structure and its Potential Applications
DNA, the molecule responsible for storing genetic information, consists of two strands of nucleotide bases coiling around each other. On these strands, different arrangements of the four sub-molecules known as “nucleotide bases” (labelled A, T, G and C) form sequences called genes. Each cell in our bodies contains almost two meters of DNA! Of these, approximately 22,000 genes are known to contain the crucial instructions for producing the proteins essential to life.
Inside each cell, a DNA molecule is coiled up to form a “chromosome”. At the end of each chromosome is a region called a “telomere”, which usually consists of the same nucleotide sequence repeated many times. At the very end of the telomere, there is an overhang of single-stranded DNA with the sequence TTAGGG repeating itself hundreds of times. Telomeres exist to protect our genetic code; whenever a chromosome is copied during cell replication, a small part at the end is typically lost in the process. So, as we age, our telomeres get shorter. This decline in length, which is slightly faster in men than in women, is a natural process; when our cells get old, their telomeres run out and our cells die.
Cancer cells, however, do not die, but replicate without control. One of the ways they achieve immortality is by keeping their telomeres long. An enzyme called telomerase, which is very active in cancer cells but usually absent in bodily cells, elongates the telomeres between cell divisions. Research into drugs that can interrupt this process has been going flourishing in the past decade.
DNA strands do not always have to form a double helix structure. Sections of DNA can form structures called “G-quadruplexes”, consisting of stacks of square sheets, each sheet consisting of four guanine (G) nucleotide bases.
G-quadruplexes exhibit a rich variety of forms that have been studied intensively since their discovery in the 1960s. Analyses of the human genome suggest that there are over 300,000 sequences capable of forming G-quadruplexes in the human body. Interestingly, these sequences occur in places on the chromosomes that are especially active in processes like DNA replication. G-quadruplexes can also form in the telomere regions at the ends of chromosomes, which are rich in guanine bases.
G-quadruplex formation in the telomeres might play an important role in the fight against cancer, for two reasons. First, their presence can act like a “knot” in the DNA strands, obstructing the action of telomerase and hence stripping cancer cells of their immortality. Second, using a similar principle, G-quadruplexes may be able to prevent the reading of harmful genes known as “oncogenes”, which code to produce cancer inducing proteins (these either increase the rate of cell divisions or prevent cell death). The goal is to find molecules that will stabilize the G-quadruplexes on formation, which will prevent the reading of these oncogenes and hopefully stop the proliferation of cancer cells. This technique would be new and promising way to treat cancer.
Because of these potential therapeutic applications, scientists have been highly motivated to study G-quadruplexes. However, much still remains to be discovered about these structures, particularly the dynamics of how they interact with other molecules.
At Nanyang Technological University, the research group of Professor Phan Anh Tuan comprises of biologists, physicist, and chemists, all working together to shed light on some of the mysteries that this molecule holds, with the aid of powerful laboratory techniques and computational tools. We should look forward to the future of this research field, because many interesting advances are sure to come!
Figure 3 Left: a G-quartet made from four guanines bases with a positive metal ion in the middle. Right: three G-quartets stacked up to form a G-quadruplex. [5]
References
1) Mihaela Pertea & Steven Salzberg (2010). “Between a chicken and a grape: estimating the number of human genes”. Genome Biology. 11 (5): 206. doi:10.1186/gb-2010-11-5-206.
2) Image source: https://www.nature.com/scitable/topicpage/discovery-of-dna-structure-and-function-watson-397
3) Image source: http://www.genesandhealth.org/genes-your-health/genes-made-easy
4) Rhodes, Daniela, and Hans J Lipps. “G-quadruplexes and their regulatory roles in biology.” Nucleic acids research vol. 43,18 (2015): 8627-37. doi:10.1093/nar/gkv862
5)Image source: http://dna-barcoding.blogspot.com/2014/12/four-stranded-dna.html
6) Huppert JL, Balasubramanian S, “Prevalence of quadruplexes in the human genome”, Nucleic Acids Res. 2005; 33(9):2908-16.
Tatsiana Kusmich won the third prize in the SPMS Science-Writing Competition 2019. She is a former exchange student of the Chemistry and Biological Chemistry programme in SPMS, and is currently based in London.
