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Protection of Mammalian Telomeres Oncogene (2002) 21, 532 ± 540 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Protection of mammalian telomeres Titia de Lange*,1 1Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10021, USA Telomeres allow cells to distinguish natural chromosome heterodimer, unable to bind DNA (Figure 1b) (van ends from damaged DNA. When telomere function is Steensel et al., 1998). This allele, TRF2DBDM, blocks the disrupted, a potentially lethal DNA damage response can accumulation of TRF2 on chromosome ends and ensue, DNA repair activities threaten the integrity of eectively strips TRF2 and its interacting factors o chromosome ends, and extensive genome instability can the telomeres (Li et al., 2000; van Steensel et al., 1998; arise. It is not clear exactly how the structure of Zhu et al., 2000). TRF2DBDM does not aect other telomere ends diers from sites of DNA damage and how telomeric DNA binding factors, such as TRF1. telomeres protect chromosome ends from DNA repair Inhibition of TRF2 in cultured human cells has been activities. What are the de®ning structural features of very informative with regard to the exact consequences telomeres and through which mechanisms do they ensure of telomere dysfunction at the cellular, chromosomal, chromosome end protection? What is the molecular basis and molecular level. From the analysis of what goes of the telomeric cap and how does it act to sequester the wrong with telomeres in the absence of TRF2, a view chromosome end? Here I discuss data gathered in the has emerged of how telomeres normally protect last few years, suggesting that the protection of human chromosome ends. chromosome ends primarily depends on the telomeric protein TRF2 and that telomere capping involves the formation of a higher order structure, the telomeric loop Cellular consequences of telomere dysfunction: or t-loop. apoptosis and senescence Oncogene (2002) 21, 532 ± 540. DOI: 10.1038/sj/onc/ 1205080 The cellular outcomes of TRF2 inhibition suggest that TRF2-depleted telomeres are perceived as if they Keywords: TRF2; telomere; p53; capping; apoptosis; represent sites of DNA damage (Karlseder et al., senescence; genome instability; ATM; DNA-PK; Ku 1999; van Steensel et al., 1998). In many cell types, including primary lymphocytes, TRF2 inhibition leads to immediate induction of apoptosis (Figure 1c) The key factor in telomere protection: TRF2 (Karlseder et al., 1999). Apoptosis is accompanied by the stabilization and activation of p53, resulting in TRF2 coats the length of all human telomeres at all expression of its downstream targets p21 and bax. The stages of the cell cycle (Figure 1a) (Bilaud et al., 1997; p53 response is required to initiate apoptosis which Broccoli et al., 1997). This small, ubiquitously does not occur in human and mouse cells lacking a expressed protein, is estimated to be present at more functional p53 pathway. In addition to p53, the ATM than 100 copies per chromosome end, binding directly PI3 kinase is required for the initiation of this to the tandem array of duplex TTAGGG repeats. The program. Two B-cell lines from ataxia telangiectasia protection of human telomeres crucially depends on patients lacking this kinase and cells from mice lacking this factor and it is reasonable to assume that the a functional ATM gene failed to show apoptosis after requirement for TTAGGG repeats at chromosome TRF2 inhbition (Karlseder et al., 1999; Karlseder and ends re¯ects the need for TRF2 binding. Indeed, de Lange, unpublished). Consistent with a role for the expression of a mutant telomerase that adds sequences ATM kinase in its activation, p53 is phosphorylated on to chromosome ends lacking TRF2 binding sites, serine 15 (Karlseder and de Lange, unpublished). The results in a deleterious phenotype similar to that of involvement of the ATM kinase in this response TRF2 inhibition (Guiducci et al., 2001; Kim et al., pathway suggests that telomeres lacking TRF2 are 2001). perceived as damaged DNA. ATM has been previously In the experiments reviewed below, inhibition of implicated in the response to g-irradiation, generally TRF2 is achieved a using dominant negative allele that believed to cause double strand breaks (DSBs) (Can- binds the endogenous TRF2 and forms an inactive man et al., 1994; Khanna and Lavin, 1993). Therefore, the loss of TRF2 from telomeres may create a structure that resembles this type of damage. When TRF2 is inhibited in G1 cells, apoptosis can *Correspondence: T de Lange, Laboratory for Cell Biology and Genetics, Box 159, The Rockefeller University, 1230 York Avenue, occur before the onset of DNA replication, indicating New York, NY 10021, USA; E-mail: [email protected] that neither telomere replication nor chromosome Telomere capping T de Lange 533 Figure 1 TRF2 and the cellular consequences of its inhibition. (a) Schematic of mammalian telomeres containing the TRF2 complex. (b) Inhibition of TRF2 using a dominant negative allele, lacking the N-terminal basic domain and the C-terminal Myb DNA binding domain, TRF2DBDM.(c) Cellular consequences of telomere deprotection due to inhibition of TRF2 segregation are required to generate the apoptotic cence rather than apoptosis (Figure 1c) (Karlseder et signal. Apparently the chromosome end is immediately al., 1999; Smogorzewska and de Lange, in prepara- altered when TRF2 is removed and this alteration leads tion). These cells display all the morphological and to activation of the ATM/p53 response pathway. molecular signs of senescence, including a large and ¯at Apoptosis also occurs when telomere dysfunction is cell shape, frequent occurrence of multiple nuclei, a 2n enforced by dierent methods. For instance, human or 4n DNA content, and staining with the senescence cells expressing a mutant telomerase generating telo- associated marker SA-b-gal (Smogorzewska and de meric repeats without TRF2 binding sites undergo Lange, in preparation). The pathway leading to this apoptosis (Guiducci et al., 2001; Kim et al., 2001) and response resembles the induction of senescence by apoptosis occurs in telomerase-de®cient mouse cells shortened telomeres, involving upregulation of p53 once the telomeres have reached a critically short length (and its target p21) as well as eects on the Rb (Chin et al., 1999). As is the case for TRF2 inhibition, pathway, including induction of the Cdk inhibitor p16 apoptosis in the telomerase de®cient mice can be by- and concomitant lack of Rb phosphorylation. passed when the mice also lack p53. However, there also The inhibitory eects of SV40 large T and HPV16 appears to be a p53-independent apoptosis response to E6 and E7 were used in order to determine the shortened telomeres. Both in the telomerase-de®cient contribution of the p53 and p16/Rb pathways to the mice and in tumor cell lines expressing a dominant senescent signal (Smogorzewska and de Lange, in negative allele of the telomerase reverse transcriptase preparation; for reviews on HPV and SV40 oncopro- eventually undergo apoptosis even when p53 is absent teins, see Pipas and Levine, 2001; Tommasino and (Chin et al., 1999; Hahn et al., 1999; Zhang et al., 1999). Crawford, 1995, respectively). When p53 was inacti- Interestingly, one of the tumor cell lines that undergoes vated with the HPV16 E6 oncoprotein or a dominant p53-independent apoptosis after prolonged telomerase negative allele of p53, TRF2DBDM could still induce a inhibition (SW613 (Hahn et al., 1999)), does not show cell cycle arrest. Similarly, inhibition of pRb with E7 an apoptotic response to TRF2DBDM (Karlseder and de failed to abrogate the cell cycle arrest. Abrogation of Lange, unpublished). Perhaps this dierential response the TRF2DBDM induced arrest was only observed in indicates that cells experiencing TRF2 inhibition cells expressing both E6 and E7 or SV40 large T sustain a dierent type of lesion or have less extensive antigen. Such cells presumably lack both the p53 and damage than when their telomeres are shortened. the Rb pathway. Apparently both tumor suppressors In a subset of human cell types, most prominently are capable of preventing entry into S phase when primary ®broblasts, TRF2 inhibition results in senes- telomeres are damaged. These ®ndings closely parallel Oncogene Telomere capping T de Lange 534 the signaling of senescence in cells undergoing replicative aging (reviewed in Lundberg et al., 2000; Sherr and DePinho, 2000), suggesting that telomeres lacking TRF2 resemble critically short telomeres. An important question concerns the signaling components upstream of p53 and p16/Rb that alert cells to telomere dysfunction. The ATM kinase is likely to be involved in the induction of senescence as well as in apoptosis. However, ®broblasts from A-T patients will still execute TRF2DBDM-induced senescence indicat- ing that this kinase is not alone in activating the response pathways (Smogorzewska and de Lange, in preparation). In fact, p53 is still upregulated in TRF2- depleted A-T ®broblasts, implicating perhaps other PI3 kinases such as the ATR or DNA-PKcs in this process. Although DNA-PKcs is not involved in the activation Figure 2 Molecular consequences of TRF2 inhibiton. The ®gure of p53 after g- or UV-induced damage (Jimenez et al., shows a speculative model for the formation of telomere fusions 1999; Rathmell et al., 1997) it is not excluded that this after inhibition of TRF2. Inhibition of TRF2 is proposed to kinase phosphorylates p53 at dysfunctional telomeres. result in the resolution of t-loops or failure to reform t-loops after DNA replication. The exposed 3' overhang or its processing Particularly suggestive in this regard is the fact that product activates DNA damage checkpoints. Loss of the 3' DNA-PKcs appears to be located at telomeres (d'Adda overhang can occur in absence of DNA replication. Alternatively, di Fagagna et al., 2001). An additional important DNA replication can create a blunt ended product through challenge is to determine the upstream component(s) leading strand DNA synthesis.
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