2. Telomerase and alternative mechanism(s) of telomere maintenance
Activation of a telomere maintenance mechanism is indispensable for the immortalization of human cells. Most cancer cells maintain their telomeres via activation of telomerase, a ribonucleoproteic complex which adds telomeric repeats at chromosome ends. In some cancers, however, telomeres are maintained in the absence of telomerase activity by one or more mechanisms that are known as alternative lengthening of telomeres (ALT). ALT cell lines can also be obtained after in vitro immortalization of telomerase-negative human fibroblasts with SV40 T antigen. These two pathways of telomere maintenance are very distinct phenotypically.
In telomerase-expressing cells (TEL+), telomere length is very homogenous and telomeres are found at the end of all chromosomes. However, in ALT cells, telomeres are very heterogeneous in length and some chromatids lack telomeres. In addition to its role in telomere length maintenance, hTERT has been reported to play non-canonical roles in the cell, including modulation of expression of genes implicated in tumorigenesis, through mechanisms that are still largely unknown. We are interested in the study of genes that are distinctly regulated in ALT and TEL+ cells. In particular, we are investigating the role of telomerase in the expression of extracellular matrix protein-encoding genes, like periostin (Tilman et al., 2007), collagen or fibronectin, and tumor-suppressor genes in human fibroblasts.
A second aspect of our research focuses on the impact of subtelomeric DNA methylation on telomere maintenance as it was proposed that lower levels of DNA methylation may increase telomeric sister-chromatid exchange, a process involved in the ALT mechanism of telomere maintenance.
To know more... (pdf chapter of the last de Duve Institute report)
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