POY 3

Telomerase Reverse Transcriptase (TERT) does not deserve your attention because it is structurally beautiful or mechanistically unique (although it is both of these things), but it deserves your recognition because of what it does.  TERT is intimately involved in the development of many cancers as well as the process of aging, and is today a major concentration in cancer research.  Regulation of TERT activity could become an effect means of treating cancers, or preventing them from ever occurring.

TERT is a member of the telomerase subgroup of proteins, is similar to other RNA and DNA polymerases, but specifically functions on the telomere portion of the DNA.  The telomere is the region of repetitive DNA found at the end (3’) of a chromosome, and functions to protect the chromosome, promoting cell health and proliferation.  It is the responsibility of TERT to add nucleotides to the end of chromosome to maintain the strand’s integrity.

Check out this video illustrating the importance of telomerase!



In order to accomplish this crucially important function telomerase possesses 2 functional units: TERT (protein subunit) and TER (RNA component). TERT is the catalytic subunit, and is intimately associated with TER. The TER subunit acts as the RNA template for the DNA synthesis of telomere regions. TERT is where the action happens. Nucleotides compliments to the template RNA enter the TERT active site where they are attached via phosphodiester linkages and become apart of the chromosome. The exact mechanism by which TERT works is not completely known, but it is known that catalytic activity is regulated by several interactions, including magnesium and manganese ion interactions with amino acid residues.


Telomerase activity is essential to cell proliferation due to the degradation of the linear ends of chromosomes in the absence of activity. Without telomerase active, cells will exit the cell cycle and enter a senescent (non-dividing) state and eventually cause cell death. The catalytic activity of TERT is necessary to maintain normal production of the many proteins and enzymes that sustain life. This function of TERT effectively slows the aging process of cells, and could potentially be used to slow human aging. However, too much TERT activity has been found to cause cancer. Telomerase overcomes one of several hurdles that a cell must jump in order to immortalize. Immortalization often leads to the development of cancer. TERT is naturally repressed to an extent in most somatic cells, but has been found to be wildly active in cancerous species. Thus TERT regulation, via inhibition seems to be a potentially powerful means of treating cancer.

From what researchers have found we have learned that TERT is a powerful enzyme, with two dramatically different effects: either prolonged lifetime or increased rate of cancer. With additional understanding of this enzyme we may be able to create and effective treatment for cancer, as well as promote healthy, long lives. Therapeutic treatments relating to telomere length are possible just around the corner! TERT should be the POY not just because of its complexity, but because by understanding TERT we have the potential to save lives!

Assignment 2. March 18, 2011

Article 1:

Structure of Tribolium castaneum telomerase catalytic subunit TERT.

Andrew Gills, Anthony p. Schuller & Emmanuel Skordalakes

Summary:

The primary literature revealing the structure of TERT in tribolium castaneum.  Telomerase is an important enzyme for maintaining telomere length in growing cells.  However, the catalytic activity ends after the cell has reached a senescent state, except in many cancerous cells.  The ability of a cell to maintain telomere integrity essentially allows the cell to become immortal.  Telomerase is intricately involved in cancer and aging.

Telomerase has two subunits: protein subunit TERT and integral RNA component (TER).  TERT is the catalytic subunit, adding DNA nucleotides to the 3’-end of chromosomes using the TER template.  The authors of the paper have determined the first high-resolution structure of the catalytic subunit TERT.  The structure contains three distinct domains named after the palm and thumb of a hand that the authors thought enzyme the enzyme resembled: TRBD (RNA-binding domain), the reverse transcriptase domain and the carboxy-terminal extension (CTE) that is thought to constitute the putative ‘thumb’ domain.  The active site consists of three aspartic acids located in the palm subdomain and adjacent fingers.  Suprisingly, TERT resembles its closest homologue HIV reverse transciptase in structure and function, suggesting an evolutionary link.  The discovered structure has potential to help develop inhibiting or activating drugs for the treatments of cancer and aging.

Article 2:

The structure and function of telomerase reverse transcriptase.

Autexier C, Lue NF.

Summary:

A comprehensive review of telomerase reverse transcriptase.  The authors discuss the significance of TERT in eukaryotic cells.  Telomeres are special nucleoproteins structures found at the end of linear chromosomes, protecting the chromosomes from degradation and promoting cell proliferation.  The catalytic activity of telomerase depends on two components; TERT and telomerase RNA.  TERT is located with the “palm” and “fingers” domain of “right hand” analogy for the structure.  TERT functions to repetitively transcribe a short segment of RNA from the template domain and adding to the same DNA substrate.  TERT function is regulated by RNA-DNA, TERT-DNA, TERT-RNA, and TERT-TERT interactions.  Metal-binding Asp and Glu residues

Are necessary to mediate two metal binding mechanism for catalysis, binding to magnesium and manganese ions.  The processivity of telomerase has been determined to temperature, substrate concentrations and , primer sequences and G-quadraplex-interacting agents.  At the time of publication the authors identified obtaining a high-resolution structure of the protein as one of the key challenges that lie ahead, and since then the structure has been determined in high-resolution was determined by Andrew Gills, Anthony p. Schuller & Emmanuel Skordalakes in the October 2008 edition of Nature.

Article 3:

Structures of telomerase subunits provide functional insights.

Sekaran VG, Soares J, Jarstfer MB.

Summary:

A review focused on recent advances in the structural biochemistry of telomerase (including the discovering of the structure of TERT catalytic subunit in beetle) and the resulting implications of cellular aging and therapeutic anti-cancer treatments.  Telomerase activity is essential to cell proliferation due to the degradation of the linear ends of chromosomes in the absence of activity.  Without telomerase active, cells will exit the cell cycle and enter a senescent state and leads to cell death.  Telomerase overcomes one of several hurdles that a cell must jump in order to immortalize.  The activity of telomerase has been directly linked to aging.  Mice with over-expression of TERT in cancer-resistant animals experienced a delay in aging and an overall prolonged lifespan.  In addition, it has been found that health lifestyle changes in humans have increased telomerase activity in the immune system cells of humans.  These findings suggest that telomerase is a “molecular fountain of youth,” also has dramatic consequences.  The vast majority of cancer cells in human tumors demonstrate telomerase activity.  The prolonged maintenance of telomerase activity has been identified as an essential pathway for the transformation of normal somatic cells to eventual malignant cells.  Thus, telomerase is becoming a major source of investigation as an anti-cancer target.  Telomerase is also involved in several other activities away from the telomere that are not yet well known.

Assignment 1 - March 2, 2011

Telomerase Reverse Transcriptase (TERT).
PDB: 3DU5

 

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