Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres

Wu, Ling; Multani, Asha S.; He, Hua; Cosme-Blanco, Wilfredo; Deng, Yu; Deng, Jian Min; Bachilo, Olga; Pathak, Sen; Tahara, Hidetoshi; Bailey, Susan M.; Deng, Yibin; Behringer, Richard R.; Chang, Sandy

doi:10.1016/j.cell.2006.05.037

Cited by 369 publications

(487 citation statements)

References 63 publications

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“…Depletion of endogenous TRF2 levels either by overexpression of dominant negative TRF2 (TRF2-DN) or through genetic knockout approaches in mouse cells with long telomeres results in massive chromosomal fusions with telomeric sequence at the sites of fusions. Mouse models in which shelterin components have been deleted experience telomere dysfunction, a DDR and chromosomal fusions resembling those observed in telomerase null mice 79,81,[84][85][86][87][88] . These results suggest that both critically short telomeres and direct disruption of the shelterin structure can initiate telomere dysfunction, trigger a DDR and chromosomal fusions.…”

Section: Box 1 the Shelterin Complexmentioning

confidence: 99%

“…TRF1 is a negative regulator of telomere length while TRF2 plays important roles in preventing a DNA damage response (DDR) at telomeres. POT1 belongs to a family of evolutionarily conserved oligosaccharide/oligonucleotide-binding (OB)-fold containing proteins and specifically recognizes the single-stranded G-overhang [78][79][80][81] . Shelterin components that do not bind telomeric DNA directly include TIN2, which associates with TRF1 and TRF2 and TPP1, which forms a heterodimer with POT1 82,83 .…”

Section: Box 1 the Shelterin Complexmentioning

confidence: 99%

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Telomere dysfunction and tumour suppression: the senescence connection

2008

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Long lived organisms such as humans have evolved several intrinsic tumor suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem cell compartments. One of these anti-cancer barriers is the telomere, a specialized nucleoprotein that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.More than 40 years ago, Hayflick and Moorhead discovered that normal human diploid fibroblasts (HDFs) cannot grow indefinitely in culture 1 . Rather, their proliferative capacities are intrinsically limited. After 60-80 population doublings in culture, HDFs stop dividing and adopt a phenotype characterized by large, flat cell size, a vacuolated morphology, inability to synthesize DNA, and the presence of the senescence-associated β-galactosidase (SA-β-gal) marker 2 . We now know that the endpoint of this proliferative limit, termed replicative senescence, is due largely to erosion of telomeres, protective structures that cap the end of all eukaryotic chromosomes. Confirmation of this came from studies in which telomerase, the enzyme that maintains telomeres, was ectopically expressed in normal human somatic cells 3,4 . Activation of telomerase results in telomere elongation, abrogation of replicative senescence, a normal karyotype and cellular immortalization. These results clearly demonstrate that telomere length determines the proliferative lifespan of HDFs, and that upregulation of telomerase activity (hence telomere length) restores proliferative capacity.A large body of experimental evidence has demonstrated that telomere attrition contributes to tumorigenesis by promoting genome instability 5 . However, in the setting of a competent p53 pathway, mouse models have recently shown that telomere shortening is also tumor suppressive by promoting replicative senescence to inhibit tumor formation. In this Perspective, we will discuss how telomeres shorten with cell replication and how this might initiate a DNA damage response to induce replicative senescence (and cell death) and ultimately prevent tumorigenesis.

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Section: Box 1 the Shelterin Complexmentioning

confidence: 99%

Section: Box 1 the Shelterin Complexmentioning

confidence: 99%

Telomere dysfunction and tumour suppression: the senescence connection

2008

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“…To examine this possibility, we monitored the status of the 3′ G-overhang in mSSB1 ∆/∆ MEFs and reconstituted cell lines using an in-gel hybridization assay [14,25]. The ratio of the ss G-overhang to total telomere did not differ appreciably in mSSB1 ∆/∆ MEFs expressing vector, mSSB1 WT , mSSB1 Y85A or mSSB1 F98A ( Figure 5D).…”

Section: Mssb1 and Mssb2 Protect Both Leading-and Laggingstrand Telommentioning

confidence: 99%

Single strand DNA binding proteins 1 and 2 protect newly replicated telomeres

Deng

Lei

et al. 2013

Cell Res

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Human single-strand (ss) DNA binding proteins 1 and 2 (hSSB1 and 2) are components of the hSSB1/2-INTS3-C9orf80 heterotrimeric protein complex shown to participate in DNA damage response and maintenance of genome stability. However, their roles at telomeres remain unknown. Here, we generated murine SSB1 conditional knockout mice and cells and found that mSSB1 plays a critical role in telomere end protection. Both mSSB1 and mSSB2 localize to a subset of telomeres and are required to repair TRF2-deficient telomeres. Deletion of mSSB1 resulted in increased chromatid-type fusions involving both leading-and lagging-strand telomeric DNA, suggesting that it is required for the protection of G-overhangs. mSSB1's interaction with INTS3 is required for its localization to damaged DNA. mSSB1 interacts with Pot1a, but not Pot1b, and its association with telomeric ssDNA requires Pot1a. mSSB1 ∆/∆ mice die at birth with developmental abnormalities, while mice with the hypomorphic mSSB1 F/F allele are born alive and display increased sensitivity to ionizing radiation (IR). Our results suggest that mSSB1 is required to maintain genome stability, and document a previously unrecognized role for mSSB1/2 in the protection of newly replicated leading-and lagging-strand telomeres.

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“…hPOT1 mainly regulates telomerase-mediated telomere extension (Colgin et al, 2003) and protect telomeres from end-to-end chromosomal fusions . In addition, hPOT1 may involved in cell cycle regulation (Wu et al, 2006), apoptosis (Wan et al, 2011) and so on. Many studies had reported that hPOT1 is correlated with a broad range of cancers, for example, gastric cancer (Wan et al, 2011), papillary thyroid cancer (Cantara et al, 2012), breast cancer (Shen et al, 2010), leukemia (Poncet et al, 2008).…”

Section: Expression Of Hpot1 In Hela Cells and The Probability Of Genmentioning

confidence: 99%

Expression of hPOT1 in HeLa Cells and the Probability of Gene Variation of hpot1 Exon14 in Endometrial Cancer are Much Higher than in Other Cancers

Liu

Pu²,

Huang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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To investigate the expression of hPOT1 in the HeLa cell line and screen point mutations of hpot1 in different tumor tissues a two step osmotic method was used to extract nuclear proteins. EMSA was performed to determine the expression of hPOT1 in the HeLa cell line. PCR was also employed to amplify the exon14 sequence of the hpot1 gene in various of cancer tissues. A SV gel and PCR clean-up system was performed to enrich PCR products. DNAStar was used to analyse the exon14 sequence of the hpot1 gene. hPOT1 was expressed in the HeLa cell line and the signal was gradually enhanced as the amount of extracted nuclear proteins increased. The DNA fragment of exon14 of hpot1 was successfully amplified in the HeLa cell line and all cancer tissues, point mutations being observed in 2 out of 3 cases of endometrial cancer (66.7%) despite the hpot1 sequence being highly conserved. However, the sequence of hpot1 exon14 do not demonstrate point mutations in most cancer tissues. Since hPOT1 was expressed in HeLa cell and the probability of gene point variants was obviously higher in endometrial cancer than other cancers, it may be involved in the pathogenesis of gynecological cancers, especially in cervix and endometrium.

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Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres

Cited by 369 publications

References 63 publications

Telomere dysfunction and tumour suppression: the senescence connection

Telomere dysfunction and tumour suppression: the senescence connection

Single strand DNA binding proteins 1 and 2 protect newly replicated telomeres

Expression of hPOT1 in HeLa Cells and the Probability of Gene Variation of hpot1 Exon14 in Endometrial Cancer are Much Higher than in Other Cancers

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