Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression Adroit targeting of these critical events should have potent and specific therapeutic consequences

Proliferation, cell cycle and apoptosis in cancer

Catalytic protein subunits of telomerase from the ciliate Euplotes aediculatus and the yeast Saccharomyces cerevisiae contain reverse transcriptase motifs. Here the homologous genes from the fission yeast Schizosaccharomyces pombe and human are identified. Disruption of the S. pombe gene resulted in telomere shortening and senescence, and expression of mRNA from the human gene correlated with telomerase activity in cell lines. Sequence comparisons placed the telomerase proteins in the reverse transcriptase family but revealed hallmarks that distinguish them from retroviral and retrotransposon relatives. Thus, the proposed telomerase catalytic subunits are phylogenetically conserved and represent a deep branch in the evolution of reverse transcriptases.

https://science.sciencemag.org/content/sci/277/5328/955.full.pdf

Telomerase catalytic subunit homologs from fission yeast and human

Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA

Every cell in a multicellular organism has the potential to die by apoptosis, but tumour cells often have faulty apoptotic pathways. These defects not only increase tumour mass, but also render the tumour resistant to therapy. So, what are the molecular mechanisms of tumour resistance to apoptosis and how can we use this knowledge to resensitize tumour cells to cancer therapy?

/pdf/death-and-anti-death-tumour-resistance-to-apoptosis-4wqqeuiefw.pdf

Death and anti-death: tumour resistance to apoptosis

https://courses.washington.edu/gs466/readings/meyerson.pdf

hEST2, the Putative Human Telomerase Catalytic Subunit Gene, Is Up-Regulated in Tumor Cells and during Immortalization

The telomerase ribonucleoprotein catalyzes the addition of new telomeres onto chromosome ends A gene encoding a mammalian telomerase homolog called TP1 (telomerase-associated protein 1) was identified and cloned TP1 exhibited extensive amino acid similarity to the Tetrahymena telomerase protein p80 and was shown to interact specifically with mammalian telomerase RNA Antiserum to TP1 immunoprecipitated telomerase activity from cell extracts, suggesting that TP1 is associated with telomerase in vivo The identification of TP1 suggests that telomerase-associated proteins are conserved from ciliates to humans

http://science.sciencemag.org/content/sci/275/5302/973.full.pdf

A mammalian telomerase-associated protein.

We have cloned and characterized a human gene encoding TP2 (telomerase-associated protein 2), a protein with similarity to reverse transcriptases and the catalytic telomerase subunits from Saccharomyces cerevisiae and Euplotes aediculatus. Indirect immunofluorescence revealed that TP2 was localized to the nucleus. Using antibodies to endogenous and epitope-tagged TP2, we found that TP2 was associated specifically with human telomerase activity and the recently identified telomerase-associated protein TP1. Mutation of conserved residues within the reverse transcriptase domain of TP2 severely reduced associated telomerase activity. These results suggest that telomerase is an evolutionarily conserved multisubunit complex composed of both structural and catalytic subunits.

/pdf/human-telomerase-contains-evolutionarily-conserved-catalytic-eguoc229vf.pdf

Human telomerase contains evolutionarily conserved catalytic and structural subunits

The presence of telomerase activity in most human tumors, but not in many normal somatic tissues, has raised considerable interest in telomerase as a possible anticancer therapy. Recent advances in the cloning and characterization of mammalian telomerase components have paved the way for a more detailed understanding of the role of telomerase and telomere length maintenance in cell proliferation. Here, we summarize the most recent biochemical and genetic evidence suggesting that telomere length maintenance by telomerase is critical to the proliferative ability of some immortalized mammalian cells in culture and in vivo.

Telomeres, telomerase, and cancer: life on the edge of genomic stability.

Ciliate and yeast telomerase possess a nucleolytic activity capable of removing DNA from the 3' end of a single-stranded oligonucleotide substrate. The nuclease activity is thought to assist in enzyme proofreading and/or processivity. Herein, we report a previously uncharacterized human telomerase-associated nuclease activity that shares several properties with ciliate and yeast telomerases. Partially purified human telomerase, either from cell extracts or recombinantly produced, demonstrated an ability to remove 3' nontelomeric nucleotides from a substrate containing 5' telomeric DNA, followed by extension of the newly exposed telomeric sequence. This cleavage/extension activity was apparent at more than one position within the telomeric DNA and was influenced by sequences 5' to the telomeric/nontelomeric boundary and by substitution with a methylphosphonate moiety at the telomeric/nontelomeric DNA boundary. Our data suggest that human telomerase is associated with an evolutionarily conserved nucleolytic activity and support a model in which telomerase-substrate interactions can occur distal from the 3' primer end.

/pdf/a-human-telomerase-associated-nuclease-3xgsxcn8k7.pdf

Rena Oulton

Papers

A mammalian telomerase-associated protein.

Human telomerase contains evolutionarily conserved catalytic and structural subunits

Telomeres, telomerase, and cancer: life on the edge of genomic stability.

A human telomerase-associated nuclease.