Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G‐strand overhang

Samper, Enrique; Goytisolo, Fermín A.; Slijepčević, Predrag; Buul, Paul P.W. van; Blasco, Marı́a A.

doi:10.1093/embo-reports/kvd051

Cited by 296 publications

(285 citation statements)

References 39 publications

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“…Consistently, mice and cells with knockouts for repair proteins were found to display telomeric phenotypes (24,31,44). In addition, components of the DNA-PK complex have been shown to mediate both chromosomal fusions and apoptosis due to critically short telomeres, in agreement with the notion that a short telomere is processed and signaled as a double-strand break (22,23,35).…”

supporting

confidence: 55%

Functional Interaction between Poly(ADP-Ribose) Polymerase 2 (PARP-2) and TRF2: PARP Activity Negatively Regulates TRF2

Dantzer

Giraud-Panis

Jaco

et al. 2004

Molecular and Cellular Biology

167

130

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The DNA damage-dependent poly(ADP-ribose) polymerase-2 (PARP-2) is, together with PARP-1, an active player of the base excision repair process, thus defining its key role in genome surveillance and protection. Telomeres are specialized DNA-protein structures that protect chromosome ends from being recognized and processed as DNA strand breaks. In mammals, telomere protection depends on the T 2 AG 3 repeat binding protein TRF2, which has been shown to remodel telomeres into large duplex loops (t-loops). In this work we show that PARP-2 physically binds to TRF2 with high affinity. The association of both proteins requires the N-terminal domain of PARP-2 and the myb domain of TRF2. Both partners colocalize at promyelocytic leukemia bodies in immortalized telomerase-negative cells. In addition, our data show that PARP activity regulates the DNA binding activity of TRF2 via both a covalent heteromodification of the dimerization domain of TRF2 and a noncovalent binding of poly(ADP-ribose) to the myb domain of TRF2. PARP-2 ؊/؊ primary cells show normal telomere length as well as normal telomerase activity compared to wild-type cells but display a spontaneously increased frequency of chromosome and chromatid breaks and of ends lacking detectable T 2 AG 3 repeats. Altogether, these results suggest a functional role of PARP-2 activity in the maintenance of telomere integrity.

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supporting

confidence: 55%

Functional Interaction between Poly(ADP-Ribose) Polymerase 2 (PARP-2) and TRF2: PARP Activity Negatively Regulates TRF2

Dantzer

Giraud-Panis

Jaco

et al. 2004

Molecular and Cellular Biology

167

130

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“…Alternatively, or in addition, the repair proteins, in concert with the telomere-associated proteins with which they interact, may suppress the inappropriate fusion or recombination of telomeres. In support of this possibility, mammalian cells deficient in Ku, components of the RMN complex, or WRN all show an increase in telomere erosion, fusions or other signs of dysfunction [80,[97][98][99].…”

Section: Telomere-associated Proteins With Non-telomeric Functionsmentioning

confidence: 95%

Cancer and aging: the importance of telomeres in genome maintenance

Rodier

Kim

Nijjar

et al. 2005

The International Journal of Biochemistry & Cell Biology

120

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Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single stranded DNA into a protective structure.

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“…We prepared metaphases for Q-FISH and hybridized them as described 12 . To correct for lamp intensity and alignment, we analyzed images from fluorescent beads (Molecular Probes) using the TFL-Telo program (gift from P. Lansdorp, Terry Fox Laboratory, Vancouver).…”

Section: Cellsmentioning

confidence: 99%

“…Q-FISH analysis alsoWe next examined whether the abnormally long telomeres present in the SUV39DN cells retained their end-capping function. Dysfunctional telomeres have been shown to result in more end-toend chromosome fusions [10][11][12][13][14][15] . Robertsonian-like (RT-like) fusions are the most common structural aberration associated with telomere dysfunction in mouse cells [10][11][12]14,15 Table 2 online).…”

mentioning

confidence: 99%

Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases

et al. 2003

Self Cite

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Telomeres are capping structures at the ends of eukaryotic chromosomes composed of TTAGGG repeats bound to an array of specialized proteins 1-3 . Telomeres are heterochromatic regions. Yeast and flies with defects in activities that modify the state of chromatin also have abnormal telomere function 4-6 , but the putative role of chromatin-modifying activities in regulating telomeres in mammals is unknown. Here we report on telomere length and function in mice null with respect to both the histone methyltransferases (HMTases) Suv39h1 and Suv39h2 (called SUV39DN mice). Suv39h1 and Suv39h2 govern methylation of histone H3 Lys9 (H3-Lys9) in heterochromatic regions 7 . We show that primary cells derived from SUV39DN mice have abnormally long telomeres relative to wild-type controls. Using chromatin immunoprecipitation (ChIP) analysis, we found that telomeres were enriched in diand trimethylated H3-Lys9 but that telomeres of SUV39DN cells had less dimethylated and trimethylated H3-Lys9 but more monomethylated H3-Lys9. Concomitant with the decrease in H3-Lys9 methylation, telomeres in SUV39DN cells had reduced binding of the chromobox proteins Cbx1, Cbx3 and Cbx5, homologs of Drosophila melanogaster heterochromatin protein 1 (HP1). These findings indicate substantial changes in the state of telomeric heterochromatin in SUV39DN cells, which are associated with abnormal telomere elongation. Taken together, the results indicate epigenetic regulation of telomere length in mammals by Suv39h1 and Suv39h2.The N-terminal tails of histones are subjected to post-translational modifications, including acetylation, methylation and phosphorylation, generating an extensive repertoire of chromatin structures 8,9 . Binding of factors that specifically recognize these modified histones mediate cellular responses 8,9 . Heterochromatic regions are enriched in methylated H3-Lys9, which creates a binding site for the chromobox proteins 9 , mediators of heterochromatin formation and epigenetic gene regulation. In D. melanogaster, HP1 is also required for telomere capping 4,5 . To investigate the impact of H3-Lys9 methylation on telomere length regulation and telomere function, we studied embryonic stem (ES) cells and mouse embryonic fibroblasts (MEFs) from SUV39DN mice 7 , which have less methylation of H3-Lys9 at the pericentric heterochromatin compared to wildtype mice 7 . First, we used terminal restriction fragment (TRF) analysis to estimate telomere length in these cells. Two independent SUV39DN ES cell cultures showed abnormally long telomeres, which were not present in wild-type ES cells (Fig. 1a). This finding was confirmed using MEFs (passage 1-2) derived from SUV39DN and wild-type littermate embryos (Fig. 1a). TRF analysis of increasing passages of the SUV39DN MEFs (D43) showed that the long telomeres in these MEFs were stable (Fig. 1b).Next, we carried out quantitative fluorescence in situ hybridization (Q-FISH) using a telomere-specific peptide nucleic acid probe. We determined the average telomere length for each ES-cell and ME...

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Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G‐strand overhang

Cited by 296 publications

References 39 publications

Functional Interaction between Poly(ADP-Ribose) Polymerase 2 (PARP-2) and TRF2: PARP Activity Negatively Regulates TRF2

Functional Interaction between Poly(ADP-Ribose) Polymerase 2 (PARP-2) and TRF2: PARP Activity Negatively Regulates TRF2

Cancer and aging: the importance of telomeres in genome maintenance

Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases

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