Home / Treatments And Diseases / The Role of Telomerase in Health and Disease

The Role of Telomerase in Health and Disease

The gene and ribo-protein known as telomerase has always been a topic of great interest, but is receiving yet more interest as a result of the role telomerase has been found to play in the progression of cancer[1]. Expression of telomerase is almost nonexistent in adults with the exception of the germ cells of the testes, and a few lines of adult stem cells. Another important exception is the placenta where telomerase is heavily expressed.

Telomerase is expressed in adults in tissues that rely on a large amount of replacement cells for healthy function. Germ line mutations to the telomerase, or it’s associated RNA component (TERC) are associated with loss of function in bone marrow, liver and lungs. [2] In particular germ line mutations can to telomerase can inhibit liver regeneration after assault by hepatitis ( b or c ) or alcoholism, leading to cirrhosis, or loss of cellular content among extra cellular matrix ( collagen ) [2]. None the less, most cells in these tissues do not express telomerase. Telomerase expression most likely belongs to a small population of stem cells

In terms of cancer, telomerase is expressed, or mis-expressed in about 90 percent of observed cases. In that sense, expression of telomerase is about as close as one can come to a formal definition of cancer. Expression of telomerase is what allows cancer cells to defeat the Hayflick limit, or become immortal. As Leonard Hayflick observed, normal somatic cells, or differentiated cells of the body undergo a finite number of divisions and then undergo senescence in which they can no longer divide.

When telomerase is expressed in a cell, such as the germ cells of the testes, the placenta, and perhaps some stem cells of hematopoetic system ( blood ) and brain, a line of cells can divide indefinitely.

Telomerase is one of the relatively few proteins known as ribo-proteins. Telomerase is hybridized with a small piece of RNA which serves as a template for the extension of the telomeres of the chromosome, or the ends that contain highly repeated sequences of DNA. Molecules that can copy RNA to DNA are called reverse transcriptases, because the normal direction of the transcription process is DNA to RNA. For that reason, transcriptase is also called telomere reverse transcriptase,or TERT. When speaking referring to the human form, the expression hTERT is often used.

Because of the limits of the DNA duplication process by DNA polymerase, each time a chromosome is copied as a result of cell division, or the cell cycle, the telomeres of the chromosome become shorter. At some point, usually about after a limit of 30 divisions, the telomeres of the chromosome are too short to continue the division process.

Much of the mystery of telomerase, is its regulation. It’s expression is controlled by a promoter that is rich in “CpG islands”. CpG islands in promoters are one of the primary forms of transcription repression in the field of epigenetics. In other words, one of the hydrogen’s on the cytosine in a CG rich region can be replaced by a methyl group. This is referred to as DNA methylation or hypermethylation. DNA methylation is one of the primary forms of control of gene expression. When the cytosines located in a gene’s promoter region are methylated, it prevents a transcription complex from forming, and as a result, transcription and expression is repressed. In the case of hTERT, expression can be stimulated by transcription factor ( and oncogene ) myc-c but also the transcription factor spl which is ubiquitously expressed.[3]. This means that in normal somatic cells, epigenetic factors are the only barrier to mis-expression of telomerase.

This relatively recent observation may open up new avenues to understanding cancer initiation and progression. Carcinogens have traditionally been evaluated on their ability to mutate DNA. New views of cancer may review a potential carcinogens ability to disrupt epigenetic factors such as CpG island hypermethylation.

That leaves at least two options as to why telomerase is so closely associated with cancer. The first is that cancer arises in highly proliferative regions of the body where telomerase may be expressed by adult stem cells naturally. The other as a result of proliferation, duplication of methylation patterns associated with telomerase are erroneously omitted, and the result is an immortal cell clone. Thus, once a cell has lost control of it’ cell cycle, and begins to express telomerase, it is no longer subject to the limits proposed by Hayflick.

Another potential alternative to consider is that environmental factors not typically closely associated with cancer such as lead, mercury and arsenic which do have the ability to disrupt epigenetic factors such as CpG island have the ability to disrupt telomerase expression and contribute to cancer initiation and progression.[4]

References

[1]Rodrigo Calado and Neal Young

Telomeres in Disease

The Scientist May 1, 2012 [full text] [2]Hartmann D,et. al.

Telomerase gene mutations are associated with cirrhosis formation.

Hepatology. 2011 May;53(5):1608-17. doi: 10.1002/hep.24217. [ Pub Med] [3]Horikawa I, Barrett JC.

Transcriptional regulation of the telomerase hTERT gene as a target for

cellular and viral oncogenic mechanisms.

Carcinogenesis. 2003 Jul;24(7):1167-76. Epub 2003 May 22.[full text] [4] Arai Y, et. al.

Epigenetic assessment of environmental chemicals detected in maternal peripheral and cord blood samples.

J Reprod Dev. 2011 Sep;57(4):507-17. Epub 2011 May 23. [Pub Med]