DNA Ligase IV-Dependent NHEJ of Deprotected Mammalian Telomeres in G1 and G2

Smogorzewska, Agata; Karlseder, Jan; Holtgreve-Grez, Heidi; Jauch, Anna; Lange, Titia de

doi:10.1016/s0960-9822(02)01179-x

Cited by 345 publications

(330 citation statements)

References 47 publications

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“…Finally, in the absence of Mec1-dependent DNA damage checkpoints 11,21,22 , broken chromosomes seem to replicate and then fuse by Rad51-or Rad59-dependent recombination to yield dicentric inversion translocations. This is in contrast to telomerase-defective mammalian cells, in which chromosome fusions and translocations in cells that escape cell cycle arrest and apoptosis because of a p53 mutation result from a ligase 4-dependent NHEJ reaction 17,23 .…”

Section: E T T E R Smentioning

confidence: 89%

“…Because nonhomologous end joining (NHEJ) proteins Ku70, Ku80 and ligase 4 promote translocations 3,4 , telomere-telomere fusions [14][15][16][17][18] and fusion of telomeres to an induced DSB 12 , we examined the role of ligase 4 in chromosome fusions. When we introduced a lig4 mutation into the rad51 tlc1, rad55 tlc1, rad59 tlc1 and tel1 tlc1 double mutants, the GCR rate was reduced to almost wild-type rates and was indistinguishable from that of the lig4 tlc1 double mutant (P > 0.14; Table 1).…”

Section: E T T E R Smentioning

confidence: 99%

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Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast

Pennaneach

Kolodner

2004

Nat Genet

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In telomerase-deficient Saccharomyces cerevisiae, telomeres are maintained by recombination. Here we used a S. cerevisiae assay for characterizing gross chromosomal rearrangements (GCRs) to analyze genome instability in post-senescent telomerase-deficient cells. Telomerase-deficient tlc1 and est2 mutants did not have increased GCR rates, but their telomeres could be joined to other DNAs resulting in chromosome fusions. Inactivation of Tel1 or either the Rad51 or Rad59 recombination pathways in telomerase-deficient cells increased the GCR rate, even though telomeres were maintained. The GCRs were translocations and chromosome fusions formed by nonhomologous end joining. We observed chromosome fusions only in mutant strains expressing Rad51 and Rad55 or when Tel1 was inactivated. In contrast, inactivation of Mec1 resulted in more inversion translocations such as the isochromosomes seen in human tumors. These inversion translocations seemed to be formed by recombination after replication of broken chromosomes.Telomeres function in replication and maintenance of chromosome ends, to prevent DNA ends from being inappropriately joined to each other and to prevent chromosome ends from activating checkpoints 1,2 . Telomeres are maintained by telomerase, which consists of the Est2 catalytic subunit, the Tlc1 RNA and other subunits 2 .Telomere maintenance also requires other proteins. These include the Tel1 protein kinase that functions in telomere protection and length regulation and proteins such as Cdc13 and Ku that target telomerase to telomeres and protect telomeres from degradation 2 . Proteins such as Pif1 help regulate telomere length 3 and prevent telomerase from adding telomeres to broken DNAs 3,4 . In telomerase-deficient S. cerevisiae cells telomeres are maintained by recombination 5,6 . Most mammalian cells lack telomerase 7 and have a limited lifespan. Immortalization and cancer progression require increased telomere maintenance capacity, either through upregulation of telomerase activity 7 or through the alternative lengthening of telomere pathway 8 .Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast L E T T E R S 612VOLUME 36 | NUMBER 6 | JUNE 2004 NATURE GENETICS RDKY5233 is a tlc1∆ type II strain. Additional relevant GCR rates include the tlc1∆ type I strain, RDKY5232 (3.1 × 10 -10 (0.9)); lig4∆ strain, RDKY3641 (1.6 × 10 -9 (9); ref. 10); tel1∆ lig4∆ strain, RDKY5238 (4.2 × 10 -9 (12)); and tel1∆ lig4∆ est2∆ strain, RDKY5240 (3.5 × 10 -9 (10)). ND, not determined.

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Section: E T T E R Smentioning

confidence: 89%

Section: E T T E R Smentioning

confidence: 99%

Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast

Pennaneach

Kolodner

2004

Nat Genet

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“…The occurrence of dicentric chromosomes, chromosome fragments and chromosomes with abnormal telomere numbers ( Figure 3B) points to the involvement of DNA breakage. Dicentric chromosomes with less than four telomere signals at the fusion site may be generated by non-homologous DNA repair following DSBs (Obe et al, 2002) or by the junction or eroded or damaged telomeres (Chan and Blackburn, 2003), consequent to defects in telomerase activity or telomere-associated proteins (Smogorzewska et al, 2002;Urushibara et al, 2004). The virus appears to interfere with the homeostasis of telomeres as strong telomere signals were increased in EBV þ compared with EBVÀ BLs and normal B-blasts ( Figure 3D), suggesting an increase in telomere length, but the underlying mechanism and the contribution of this abnormality to the generation of chromosome breaks are not clear.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus promotes genomic instability in Burkitt's lymphoma

et al. 2007

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Epstein-Barr virus (EBV) has been implicated in the pathogenesis of human malignancies but the mechanisms of oncogenesis remain largely unknown. Genomic instability and chromosomal aberrations are hallmarks of malignant transformation. We report that EBV carriage promotes genomic instability in Burkitt's lymphoma (BL). Cytogenetic analysis of EBVÀ and EBV þ BL lines and their sublines derived by EBV conversion or spontaneous loss of the viral genome revealed a significant increase in dicentric chromosomes, chromosome fragments and chromatid gaps in EBV-carrying cells. Expression of EBV latency I was sufficient for this effect, whereas a stronger effect was observed in cells expressing latency III. Telomere analysis by fluorescent in situ hybridization revealed an overall increase of telomere size and prevalence of telomere fusion and double strand-break fusion in dicentric chromosomes from EBV þ cells. Phosphorylated H2AX, a reporter of DNA damage and ongoing repair, was increased in virus-carrying cells in the absence of exogenous stimuli, whereas efficient activation of DNA repair was observed in both EBV þ and EBVÀ cells following treatment with etoposide. These findings point to induction of telomere dysfunction and DNA damage as important mechanisms for EBV oncogenesis.

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“…Telomeres might fuse with doublestrand breaks in cells lacking telomerase and/or with eroded telomeres (Chan and Blackburn, 2003). Thirdly telomeres themselves could fuse if they were dysfunctional, lacking TRF2 (Smorgorzewska et al, 2002) or if they were damaged by single-strand breaks (see Urushibara et al, 2004).…”

Section: Metal-induced Genomic Instabilitymentioning

confidence: 99%

Effects of hTERT on metal ion-induced genomic instability

et al. 2006

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There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longerterm genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERTÀ cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased b-galactosidase staining and apoptosis. This instability was not present in telomerasepositive hTERT þ cells. In contrast, in hTERT þ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERTÀ cells. The growth and survival of both metal-exposed hTERT þ and hTERTÀ cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

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DNA Ligase IV-Dependent NHEJ of Deprotected Mammalian Telomeres in G1 and G2

Cited by 345 publications

References 47 publications

Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast

Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast

Epstein–Barr virus promotes genomic instability in Burkitt's lymphoma

Effects of hTERT on metal ion-induced genomic instability

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