Chromatin Structure of Mammalian Telomeres 11 Telomeric DNA

Vertebrate telomeres end in a single-stranded 3'overhang of the G-rich DNA strand (de Lange et al. 2002; see Dillin and Karlseder, this volume), which is thought to be generated by mechanisms that involve the postreplicative processing of the leading-strand telomere (Bailey et al. 2001) and provides the substrate for telomerase (Blackburn 2001, Chan and Blackburn 2002). The overhang is bound by a single-strand telomere binding protein known as protection of telomeres 1 (Potl) (Fig. 12.1), which has been proposed to regulate the access of telomerase to the telomere (Baumann and Cech 2001). Pot1 interacts with TPP1 and the two proteins are thought to form a heterodimer that is involved in telomere length regulation (Ye et al. 2004, Liu et al. 2004). In addition, the G-strand overhang can fold back and invade the double-stranded region of the telomere, generating a looped structure known as the telomere loop or t-loop (Griffith

Maria A. Blasco

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 3 Melchor Fern√°ndez Almagro, Madrid E-28029, Spain. e-mail: [email protected]

K.L. Rudolph (ed.), Telomeres and Telomerase in Ageing, Disease, and Cancer. © 2008 Springer-Verlag Berlin Heidelberg

telomeres

Shelterin/telosome

Shelterin/telosome subtelomeres

G-strand overhang

telomerase

G-strand overhang

telomerase

TTAGGG TTAGGG = AATCCC AATCCC"

ALT mechanisms (based in HR)

Fig. 12.1 Structure of mammalian telomeres. Double-stranded telomeric repeats are bound by a multiprotein complex known as shelterin or the telosome, which comprises TRF1, TRF2, Tin2, Rap1, Pot1, and TPP1. The G-strand overhang is also bound by the Pot1/TPP1 heterodimer. Telomerase is able to recognize the 3'end of the G-strand overhang and to elongate telomeres. In telomerase-negative cells, telomeres can be maintained by mechanisms involving homologous recombination between telomeric repeats, the so-called alternative lengthening of telomeres or ALT (See Color Plate)

et al. 1999), which provides telomere protection by sequestering the 3' end of telomeres from repair and degradation activities. t-loops resemble intermediates of homologous recombination and may be processed by activities involved in this DNA repair pathway, such as the XRCC3 protein (de Lange 2004, Wang et al. 2004).

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