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Review
. 2008 Jan 15;22(2):125-40.
doi: 10.1101/gad.1626908.

DNA damage response at functional and dysfunctional telomeres

Maria Pia Longhese  1
Affiliations
Review

DNA damage response at functional and dysfunctional telomeres

Maria Pia Longhese. Genes Dev. .

Abstract

The ends of eukaryotic chromosomes have long been defined as structures that must avoid being detected as DNA breaks. They are protected from checkpoints, homologous recombination, end-to-end fusions, or other events that normally promote repair of intrachromosomal DNA breaks. This differentiation is thought to be the consequence of a unique organization of chromosomal ends into specialized nucleoprotein complexes called telomeres. However, it is becoming increasingly clear that proteins governing the DNA damage response are intimately involved in the regulation of telomeres, which undergo processing and structural changes that elicit a transient DNA damage response. This suggests that functional telomeres can be recognized as DNA breaks during a temporally limited window, indicating that the difference between a break and a telomere is less defined than previously assumed.

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Figures

Figure 1.
Figure 1.
How chromosome end protection can be achieved. (A, top) In humans, telomeres folding into t-loops may protect the chromosome ends from NHEJ and HR. Moreover, t-loop structures may also inhibit the recruitment of telomerase and checkpoint proteins. (Bottom) For telomeres that do not adopt a t-loop conformation, the ssDNA-binding protein POT1 is thought to inhibit both ATR activation by blocking RPA recruitment to the telomeric ssDNA, and telomerase action. The dsDNA-binding protein TRF2 is proposed to prevent ATM activation. (B) In S. cerevisiae, Rap1 is thought to inhibit the recruitment of MRX, RPA, Mec1, and telomerase at telomeres, whereas Cdc13 binding to single-stranded telomere sequences prevents nucleases from binding, therefore inhibiting RPA recruitment and subsequent Mec1-dependent checkpoint activation.
Figure 2.
Figure 2.
DNA damage response to DSBs and dysfunctional telomeres. (A) Intrachromosomal DSBs trigger a DNA damage checkpoint response. When a DSB occurs, the MRX complex and other factors localize to the unprocessed break. DSB recognition by MRX allows checkpoint activation by recruiting Tel1. Tel1 in turn phosphorylates Sae2, which is recruited to DSB ends independently of MRX. MRX, Sae2, and Tel1 contribute to resection of DSB ends by exonucleases to generate 3′-ended ssDNA tails coated by RPA, which allow the loading of Mec1–Ddc2 and subsequent Mec1-dependent checkpoint activation. Mec1 activation is also supported by independent loading of the PCNA-like Ddc1–Rad17–Mec3 complex by Rad24-RFC. (B) Full-length telomeres are protected from checkpoint activation. The presence of ssDNA- and dsDNA-binding proteins on full-length chromosomal ends inhibits recruitment of MRX, RPA, nucleases, telomerase, and checkpoint proteins. (C,D) Telomeres lose protection after loss of telomeric ssDNA- and dsDNA-binding proteins (uncapped telomere) or telomerase (eroded telomere). (C) In the absence of the ssDNA-binding protein Cdc13, telomerase recruitment is impaired, and nucleases can access the chromosome end. This leads to C-rich strand degradation and accumulation of RPA-bound ssDNA, which elicits activation of a Mec1-dependent DNA damage checkpoint response. (D) RPA-bound ssDNA accumulates at telomeres also after telomere erosion due to telomerase loss. The S. cerevisiae nomenclature is used. Green arrows indicate phosphorylation events.
Figure 3.
Figure 3.
Contribution of DNA damage checkpoint proteins to telomere homeostasis regulation. (A) In S. cerevisiae, the access at full-length telomeres of telomerase, Tel1-MRX, and nucleases is inhibited. As telomere length declines, MRX and Tel1 promote the recruitment of telomerase at telomeres by phosphorylating the ssDNA-binding protein Cdc13, which mediates telomerase recruitment. (B) In humans, MRN and ATM promote telomerase-dependent telomere elongation by phosphorylating TRF1 on shortened telomeres. Phosphorylated TRF1 dissociates from telomeres, thus promoting telomerase access. In both yeast and humans, the subsequent telomere elongation increases the loading on telomeres of Rap1–Rif1–Rif2 and shelterin proteins, respectively, which can in turn block Tel1/ATM from acting, thus resulting in telomere reprotection. Green arrows indicate phosphorylation events.
Figure 4.
Figure 4.
A model for the generation of transient DNA damage signals at functional telomeres. During the G1 cell cycle phase, neither short nor full-length telomeres are susceptible to be elongated by telomerase. They are also inert for processing events by nucleases. After completion of DNA replication in late S phase and during the ensuing G2 phase, telomeres become susceptible to Clb–CDK1-dependent nucleolytic processing, which can generate RPA-coated ssDNA. During this time, telomeres share many features with DSBs. Telomeres with short TG tracts become preferentially suitable to be processed and bound by MRX. RPA-coated ssDNA generation and telomere-bound MRX can activate a transient Mec1- and Tel1-dependent checkpoint, which in turn promotes telomere elongation by phosphorylating Cdc13. Telomere elongation increases the amount of proteins bound to TG tracts, and this change blocks telomerase and Mec1/Tel1 recruitment. A functional cap could be reassembled in the next G1, when Clb–CDK1 activity is low. Green arrows indicate phosphorylation events.
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