Introduction

The production of billions of new blood cells every day in a human being depends on the undisturbed function of hematopoietic stem cells (HSCs), which represent only about 0.01% of the entire bone marrow cells (Lansdorp et al. 1997). The maintenance of the complex hematopoietic system requires a well-balanced self-renewal and differentiation of HSCs during the entire life span. However, the proliferative life span defining the self-renewal capacity of HSCs appears not to be unrestricted (Lansdorp 1995). A fundamental determinant for the proliferation potential is found in the telomeres, specialized nucleoprotein complexes protecting the ends of eukary-otic chromosomes (reviewed in Blackburn 2001). Telomeres consist of repeated units of G-rich sequences (TTAGGG in humans) that pass in a single-stranded 3' overhang and that contribute together with telomere-binding proteins to a higher-order

Uwe M Martens

Medical University Centre Freiburg, Department of Hematology/Oncology, D-79106, Freiburg, Germany.

e-mail: [email protected]

K.L. Rudolph (ed.), Telomeres and Telomerase in Ageing, Disease, and Cancer. © 2008 Springer-Verlag Berlin Heidelberg terminal loop (t-loop) structure (Blackburn 2001, Griffith et al. 1999). The number of telomeric repeats varies between different species and within an organism; in humans the telomere length is in the range from 2 to 15 kb (Martens et al. 1998). About 50-100 base pairs (bp) of telomeric DNA are lost with each cell division due to the end replication problem (Watson 1972), nucleolytic processing of the 5' strand (Lingner et al. 1995), and oxidative damage (von Zglinicki et al. 1995). Maintenance of functional telomeres is crucial for continued proliferation, given that telomere erosion is associated with replicative senescence. Most eukaryotic cells depend on the enzyme telomerase, a reverse transcriptase, for the de novo synthesis of telomeres (reviewed in Cech 2004). Telomerase is a ribonucleoprotein complex, which uses its RNA component (TERC) as a template for the production of telomeric repeats via the catalytic subunit TERT (Greider and Blackburn 1989). Telomerase activity in normal human cells is generally undetectable leading to successive telomere shortening with each cell division, which ultimately limits their proliferative capacity in vitro and most likely in vivo (Harley et al. 1990). Immortal cells like germ line cells (Allsopp et al. 1992), embryonic stem cells (Thomson et al. 1998), and 90% of all tumor cells in humans (Kim et al. 1994) maintain their telomeres by activated telomerase, thus providing an unrestricted life span. Overexpression of hTERT, the catalytic subunit of telomerase, can restore telomer-ase activity in various human cells (e.g., fibroblasts, hepatocytes, mesenchymal stem cells), which leads to maintenance of telomeres and immortal proliferation (Bodnar et al. 1998, Vaziri and Benchimol 1998, Zimmermann et al. 2004).

The telomere biology of adult stem cells found in highly proliferative tissues such as blood appears to be more complex, because telomeres shorten despite the presence of telomerase activity (see Artandi, this volume).

0 0

Post a comment