Article 1:
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.
