Functional links between telomeres and proteins of the DNA-damage response

Abstract

In response to DNA damage, cells engage a complex set of events that together comprise the DNA-damage response (DDR). These events bring about the repair of the damage and also slow down or halt cell cycle progression until the damage has been removed. In stark contrast, the ends of linear chromosomes, telomeres, are generally not perceived as DNA damage by the cell even though they terminate the DNA double-helix. Nevertheless, it has become clear over the past few years that many proteins involved in the DDR, particularly those involved in responding to DNA double-strand breaks, also play key roles in telomere maintenance. In this review, we discuss the current knowledge of both the telomere and the DDR, and then propose an integrated model for the events associated with the metabolism of DNA ends in these two distinct physiological contexts.All organisms respond to interruptions in the DNA double-helix by promptly launching the DNA-damage response (DDR). This involves the mobilization of DNArepair factors and the activation of pathways, often termed checkpoint pathways, which temporarily or permanently delay cell cycle progression. Although the integrity of the DNA double-helix is perturbed by telomeres (the ends of linear chromosomes), these structures generally escape activating the DDR. Several explanations have been proposed to explain the exceptional nature of telomeres in this regard. Thus, it has been suggested that a telomere might not be recognized by components of the DDR because of its unique DNA sequence and structure, its specific localization within the cell nucleus, and/or because of the actions of specific proteins associated with it. Although this is partly correct, recent findings have revealed that, contrary to initial expectations, various proteins involved in the DDR physically associate with telomeres and actually play important roles in regulating normal telomeric functions. In this review, we focus on the role of DDR factors in regulating telomere length and stability, and also explain how dysfunctional telomeres can trigger the DDR. Before doing this, however, we first summarize the salient features of both telomeres and the DDR. Telomere structure and biologyThe ends of linear chromosomes contain long stretches of DNA tandem repeats (TTAGGG in vertebrates) and terminate in a 3Ј protruding single-stranded DNA overhang. Due to the inability of the standard lagging-strand DNA replication machinery to copy the most distal telomere sequences (i.e., those at the very end of the chromosome) and to the additional exonucleolytic processing needed to generate protruding overhangs at both ends, telomeric DNA progressively decreases in length as cells go through successive division cycles. Hence, in the absence of specialized telomere homeostatic mechanisms this would ultimately lead to the loss of all telomeric sequences and subsequently to the loss of more internal essential genetic information and ensuing cell death. To circumvent this, many cells maintain their telomeres by the action of telo...

DNA damage signalling guards against activated oncogenes and tumour progression

“…Accumulating evidence indicates that senescence can be induced by diverse insults, including a range of DNA damaging agents and a wide spectrum of activated oncogenes, and by telomere shortening that causes the so-called replicative senescence (d'Adda di Fagagna et al, 2004;Campisi and d'Adda di Fagagna, 2007;Finkel et al, 2007). Most relevant to the topic of this review article, the phenomenon of cellular senescence also represents an emerging physiological tumour suppressive mechanism and a potential correlate of tissue ageing (Finkel et al, 2007).…”

A Point Mutation in theAspergillus nidulans sonBNup98 Nuclear Pore Complex Gene Causes Conditional DNA Damage Sensitivity

“…It will therefore be interesting to determine if telomeric localization and/ or function is disrupted in sonB1 mutants and whether this contributes to the DNA damage sensitivity of sonB1 mutants. Further, given that the MRN complex functions in telomere regulation (Verdun et al 2005; for review see d'Adda di Fagagna et al 2004), it is possible that the synthetic lethality between sonB1 and scaA NBS1 mutants may be due to combining different defects in telomere biology caused by these mutations. Another explanation for the DNA-damage-sensitive phenotype of sonB1 is that some aspect of nucleocytoplasmic transport required for the damage response does not function in this mutant at 42°.…”

The Caenorhabditis elegans Rad17 Homolog HPR-17 Is Required for Telomere Replication

“…Metaphase spreads of both human and mouse cells lacking RAD9, RAD1, or HUS1 display increased levels of chromosome abnormalities such as chromatid breaks, aneuploidy, dicentrics, and telomere loss, and multiple abnormalities are observed within a single cell (Weiss et al 2000;Bao et al 2004;Pandita et al 2006). Thus, the chromosomal dysfunction observed in mammalian cells deficient for the 9-1-1 complex or RAD17 may produce indirect effects on telomere stability, perhaps as a consequence of recruitment of DNA damage response proteins that facilitate telomere capping to unrepaired sites of endogenous DNA damage (d'Adda di Fagagna et al 2004). Alternatively, the mammalian 9-1-1 complex may play an additional telomerase-independent function in telomere length homeostasis.…”

“…A number of proteins aside from the telomerase holoenzyme play roles in telomere maintenance (Collins 2006). Some of these proteins also respond to DNA damage, suggesting dual roles in preserving the integrity of the genome (d'Adda di Fagagna et al 2004).…”