Telomerase in the human organism

Abstract

The intent of this review is to describe what is known and unknown about telomerase in somatic cells of the human organism. First, we consider the telomerase enzyme. Human telomerase ribonucleoproteins undergo at least three stages of cellular biogenesis: accumulation, catalytic activation and recruitment to the telomere. Next, we describe the patterns of telomerase regulation in the human soma. Telomerase activation in some cell types appears to o set proliferation-dependent telomere shortening, delaying but not defeating the inherent mitotic clock. Finally, we elaborate the connection between telomerase misregulation and human disease, in the contexts of inappropriate telomerase activation and telomerase de®ciency. We discuss how our current perspectives on telomerase function could be applied to improving human health.

Telomere and telomerase in stem cells

“…Stem cells are capable of generating a very large number of committed progenitors and their descendants during a small number of self-renewal divisions. As such, individual stem cell turnover at any given point would be minimal and the upregulation of telomerase activity in stem cells could be minimal, preventing the generation of overly long telomeres (Collins and Mitchell, 2002). Transient activation of telomerase activity induced during periods of rapid cellular proliferation could reduce telomere loss in lineage-committed progenitor cells.…”

“…During a process of DNA synthesis and cell division, telomeres shorten as a result of the incomplete replication of linear chromosomes, the so-called 'end-replication problem'. This progressive telomere shortening is one of the molecular mechanisms underlying ageing, as critically short telomeres trigger chromosome senescence and loss of cell viability (Collins and Mitchell, 2002;Blasco, 2005;Wright and Shay, 2005). To prevent degradation by exonucleases or processing as damaged DNA, the telomere 3 0 single-strand overhang folds back into the D-loop of duplex telomeric DNA to form a protective 'T-loop', which is reinforced with TRF2 and other telomeric DNA-binding proteins named Shelterin (de Lange, 2005).…”

Genetic variation in five genes important in telomere biology and risk for breast cancer

“…This hypothesis was investigated in a population-based case -control study of breast cancer study in Poland, in which we genotyped 24 common SNPs that captured most of the common genetic variation in five genes important in telomere biology. The studied genes included telomerase (TERT (protein name), TERT (HUGO gene name), 5p15.33) (Collins and Mitchell, 2002), telomerase-associated protein (TP1, TEP1, 14q11.2) (Poderycki et al, 2005), telomeric repeat-binding factor 1 (TRF1, TERF1, 8q13) (Smogorzewska et al, 2000), telomeric repeat-binding factor 2 (TRF2, TERF2, 16q22.1) (Chong et al, 1995;Broccoli et al, 1997) and protection of telomeres 1 (POT1, POT1, 7q31.33) (Baumann and Cech, 2001). …”

Telomere length measurements in leukocyte subsets by automated multicolor flow‐FISH

“…Telomeres are distinctive protein-DNA structures at the end of the chromosomes that are essential for maintaining the integrity and stability of the genome (1)(2)(3). To counteract the loss of telomere repeats with each cell division, germline cells, highly proliferating cells from the skin, the gut and hematopoietic tissues as well as tumor cells express telomerase, an enzyme complex with reverse transcriptase activity, which adds new telomere repeats onto chromosome ends (4,5).…”