Telomeres and cardiovascular disease

Published on July 31, 2018   43 min

A selection of talks on Clinical Practice

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I'm Dr. Jess Buxton, I'm a geneticist at University College London. This talk is on the role of "Telomeres and Cardiovascular Disease".
I'll start with an outline of what telomeres are, and the role of the enzyme telomerase in telomere function before covering telomeres and their role in monogenic disease and their role in normal aging and then the rest of the talk will focus on the role of telomeres and in particular telomere length and its role in risk of cardiovascular disease.
So, what are telomeres? Well, they're the protective caps found at the ends of all linear chromosomes, in this picture here they've been stained with a fluorescent dye.
So, telomeres are composed of repetitive sequences of DNA, these are all G rich but are different in different species. In jellyfish it's TTAGGG and that also happens to be the same as all vertebrates including humans, but it's not just one copy of this repeat unit it's many thousands and it's there to act as a buffer to protect the coding sequences. Every time a cell divides, it will lose a little bit of the DNA from the ends of all its chromosomes because of the way DNA is replicated. The cell's DNA replication machinery can't quite copy to the end of one half of the double helix strand, so a little bit is lost, this is known as the end replication problem. So, to prevent this eroding the coding sequences, the genes and regulatory sequences, the telomeric DNA is there and acts as a buffer so that is lost rather than the coding sequences in the rest of the chromosome.
So, in vertebrates including humans, telomeres are composed of many units of the six base pair repeat TTAGGG bound to a complex of proteins known collectively a shelterin, six core proteins and several additional proteins, as you can see in this diagram. Shelterin serves to protect the telomeric DNA and prevent the cells DNA repair mechanisms from recognizing the ends of linear chromosomes as double-stranded DNA breaks. So, they prevent chromosome fusion. So, in addition to their buffering function whereby every time a cell divides a little bit of the telomeric DNA is lost, with the addition of the shelterin complex it's also preventing fusion, so they're preventing both degradation and fusion. So, telomeres are absolutely crucial for genomic integrity of the cell. So, as I've mentioned in most cells, every time the cell divides in most tissues, the telomeres we'll get a little bit shorter every time. This isn't the case in some cell types particularly germ cells and stem cells, where an enzyme called telomerase is able to replace telomeric DNA repeats and it does this using its own RNA template. It's unusual enzyme that it's composed of both an RNA molecule known as TERT which provides a template to add on additional telomeric DNA repeat units and the TERT protein which is a reverse transcriptase. It's active in germ cells and stem cells to maintain the telomeres in those cell types. Telomerase is also reactivated in around 90 percent of cancer cells and this is how cancer cells become immortal and don't die out and become senescent as other cell types do.