SURVEY AND SUMMARY Telomeres, chromosome instability and cancer

Telomeres are composed of repetitive G-rich sequence and an abundance of associated proteins that together form a dynamic cap that protects chromosome ends and allows them to be distinguished from deleterious DSBs. Telomere-associated proteins also function to regulate telomerase, the ribonucleoprtotein responsible for addition of the species-specific terminal repeat sequence. Loss of telomere function is an important mechanism for the chromosome instability commonly found in cancer. Dysfunctional telomeres can result either from alterations in the telomere-associated proteins required for end-capping function, or from alterations that promote the gradual or sudden loss of sufficient repeat sequence necessary to maintain proper telomere structure. Regardless of the mechanism, loss of telomere function can result in sister chromatid fusion and prolonged breakage/fusion/bridge (B/F/ B) cycles, leading to extensive DNA amplification and large terminal deletions. B/F/B cycles terminate primarily when the unstable chromosome acquires a new telomere, most often by translocation of the ends of other chromosomes, thereby providing a mechanism for transfer of instability from one chromosome to another. Thus, the loss of a single telomere can result in on-going instability, affect multiple chromosomes, and generate many of the types of rearrangements commonly associated with human cancer. TELOMERES AND THEIR FUNCTIONS Telomeres, unique structures at the physical ends of linear eukaryotic chromosomes, were first described almost 70 years ago by Hermann Muller in his classic studies of the fruit fly Drosophilia melanogaster (1). He noted that chromosomal inversions resulting from ionizing radiation (IR)-induced double-strand breaks (DSBs) never involved the very end of a chromosome rejoining with some other part of a chromosome. Muller coined the term ‘telomere’, which comes from Greek—telos meaning end and meros meaning part— based on this chromosome end protection phenomenon. Shortly thereafter, Barbara McClintock observed that while broken ends of maize chromosome fused, forming dicentric chromosomes, unbroken chromosomes rarely fused; i.e. natural chromosomal termini are not ‘sticky’ (2). The absence of interstitial telomere sequence within IR-induced dicentrics was later verified in human cells (3). These studies demonstrate that normally cells accurately distinguish telomeric ends from random DSB ends and protect the former from illegitimate end-joining reactions. How cells make this critical distinction continues to be an active area of research today, especially as the dividing lines between the two types of ends have become less, rather than more clear. Recent discoveries that certain DSB repair proteins act to preserve—rather than to join—the natural ends of mammalian chromosomes (4–7), have provided impetus for the union of two seemingly disparate scientific fields, DNA repair and telomere biology. Here, we focus on the creation of dysfunctional mammalian telomeres in various repair deficient backgrounds that result from either the loss of end-capping structure or the loss of terminal sequence (shortening), and the consequences of this loss of function. Telomeres serve multiple functions in preserving chromosome stability, including protecting the ends of chromosomes from degradation and preventing chromosomal end fusion. The DNA component of telomeres consists of tandem arrays of short, repetitive G-rich sequence [TTAGGG in vertebrates, (8,9)], oriented 50-to-30 towards the end of the chromosome (10), ending in an essential 30 single-stranded overhang that ranges in length from 50 to 400 nt (11–13). Electron microscopy studies suggest this overhang can loop back and integrate into the duplex repeat tract, forming a ‘t-loop’ (14), an attractive, although not necessarily exclusive, architectural solution to the end-capping dilemma. *To whom correspondence should be addressed. Tel: 970 491 2944; Fax: 970 491 7742; Email: [email protected] The Author 2006. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact [email protected] 2408–2417 Nucleic Acids Research, 2006, Vol. 34, No. 8 doi:10.1093/nar/gkl303 Published online May 8, 2006