DNA damage-induced phosphorylation of the human telomere-associated protein TRF2

Tanaka, Hiromi; Mendonca, Marc S.; Bradshaw, Paul S.; Hoelz, Derek J.; Malkas, Linda H.; Meyn, M. Stephen; Gilley, David

doi:10.1073/pnas.0507915102

Cited by 81 publications

(107 citation statements)

References 44 publications

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“…The volatility of TRF2 might also be explained by its versatility in function. For instance, TRF2 has been reported to become phosphorylated ORIGINAL ARTICLE and to relocate upon induction of DNA damage (61,62). The characteristic of forming di-and oligomers and interactions with different proteins might also explain their dual binding kinetics.…”

Section: Discussionmentioning

confidence: 99%

Controlled light exposure microscopy reveals dynamic telomere microterritories throughout the cell cycle

et al. 2008

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Telomeres are complex end structures that confer functional integrity and positional stability to human chromosomes. Despite their critical importance, there is no clear view on telomere organization in cycling human cells and their dynamic behavior throughout the cell cycle. We investigated spatiotemporal organization of telomeres in living human ECV-304 cells stably expressing telomere binding proteins TRF1 and TRF2 fused to mCitrine using four dimensional microscopy. We thereby made use of controlled light exposure microscopy (CLEM), a novel technology that strongly reduces photodamage by limiting excitation in parts of the image where full exposure is not needed. We found that telomeres share small territories where they dynamically associate. These territories are preferentially positioned at the interface of chromatin domains. TRF1 and TRF2 are abundantly present in these territories but not firmly bound. At the onset of mitosis, the bulk of TRF protein dissociates from telomere regions, territories disintegrate and individual telomeres become faintly visible. The combination of stable cell lines, CLEM and cytometry proved essential in providing novel insights in compartment-based nuclear organization and may serve as a model approach for investigating telomere-driven genome-instability and studying long-term nuclear dynamics. ' 2008 International Society for Advancement of Cytometry Key termstelomere; TRF1; TRF2; nuclear organization; chromatin dynamics; CLEM; live cell imaging TELOMERES are the natural ends of linear chromosomes. A mammalian telomere consists of a double stranded array of simple TTAGGG repeats ending in a single stranded overhang that folds back to form a T-loop structure (1). In combination with sufficient telomere repeats, a complex of indirect and direct telomere binding proteins, dubbed shelterin, assures proper telomere structure and function. The specificity of shelterin for telomeric DNA is due to the recognition of TTAGGG repeats by three of its components: the homodimers telomeric repeat binding factor 1 and 2 (TRF1 and TRF2) that bind the duplex part of telomeres, and protection of telomeres 1 that binds to the single stranded TTAGGG repeats present at the three-overhang and in the D loop of the T-loop configuration (2-5).The nucleus has a meticulous organization with functional relevance to the cell assuring proper gene expression, replication and genome stability (6-8). Telomeres are considered to play an important role in spatial genome organization. Whereas yeast telomeres are known to form few large silencing clusters at the heterochromatic nuclear periphery (9,10), there is no consensus on how telomeres are organized in the mammalian nucleus. From an architectural point of view, human telomeres have been proposed to be anchored to a nuclear scaffold, thereby possibly providing struc-

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Section: Discussionmentioning

confidence: 99%

Controlled light exposure microscopy reveals dynamic telomere microterritories throughout the cell cycle

et al. 2008

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“…TRF2 localizes to DSB sites at the early stages of cellular response to DSBs, appearing in the first few seconds after DSB induction and leaving as DSBs are being processed (7). TRF2 is phosphorylated by ATM in response to DNA damage (8). The phosphorylated form of TRF2 is not bound to telomeric DNA and is localized to DNA damage sites (8).…”

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“…In addition to evidence of TRF2's role in telomere maintenance, there are multiple pieces of evidence that implicate TRF2 in double-strand break (DSB) repair of nontelomeric DNA (7)(8)(9). TRF2 localizes to DSB sites at the early stages of cellular response to DSBs, appearing in the first few seconds after DSB induction and leaving as DSBs are being processed (7).…”

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TRF2 is required for repair of nontelomeric DNA double-strand breaks by homologous recombination

Mao

Seluanov

Jiang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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TRF2 (telomeric repeat binding factor 2) is an essential component of the telomeric cap, where it forms and stabilizes the T-loop junctions. TRF2 forms the T-loops by stimulating strand invasion of the 3 overhang into duplex DNA. TRF2 also has been shown to localize to nontelomeric DNA double-strand breaks , but its functional role in DNA repair has not been examined. Here, we present evidence that TRF2 is involved in homologous recombination (HR) repair of nontelomeric double-strand breaks. Depletion of TRF2 strongly inhibited HR and delayed the formation of Rad51 foci after ␥-irradiation, whereas overexpression of TRF2 stimulated HR. Depletion of TRF2 had no effect on nonhomologous end-joining, and overexpression of TRF2 inhibited nonhomologous end-joining. We propose, based on our results and on the ability of TRF2 to mediate strand invasion, that TRF2 plays an essential role in HR by facilitating the formation of early recombination intermediates.DNA repair ͉ telomeres T RF2 (telomeric repeat binding factor 2) was first identified as a major telomere binding protein that shields chromosome ends from degradation and from end-to-end fusions (1-3). Mammalian telomeres form large duplex loops in which the single-stranded 3Ј end is embedded within the double-stranded DNA (4). TRF2 generates T-loop structures and recently was shown to bind to DNA junctions (4, 5). The mechanism by which TRF2 facilitates folding of telomeric DNA into T-loops involves binding of TRF2 complexes to DNA and untwisting the neighboring DNA, thereby favoring strand invasion (6).In addition to evidence of TRF2's role in telomere maintenance, there are multiple pieces of evidence that implicate TRF2 in double-strand break (DSB) repair of nontelomeric DNA (7-9). TRF2 localizes to DSB sites at the early stages of cellular response to DSBs, appearing in the first few seconds after DSB induction and leaving as DSBs are being processed (7). TRF2 is phosphorylated by ATM in response to DNA damage (8). The phosphorylated form of TRF2 is not bound to telomeric DNA and is localized to DNA damage sites (8). In turn, overexpression of TRF2 inhibits autophosphorylation of ATM and induction of DNA damage response (9).DSBs are repaired by two major pathways: homologous recombination (HR) and nonhomologous end-joining (NHEJ). During HR, the missing information is copied into the DSB site from a homologous sequence, whereas NHEJ joins the broken ends without homology. Several proteins involved in DSB repair interact with TRF2, such as the MRE11/Rad50/NBS1 complex, Ku70, WRN, and BLM (10-12). Thus, TRF2 is phosphorylated in response to DNA damage, localizes to DNA breaks, and interacts with DSB repair proteins, but its functional role in DSB repair is unknown. Here, we examined the role of TRF2 in DSB repair by HR and NHEJ. ResultsReporter Cell Lines for Detection of NHEJ and HR. To study the role of TRF2 in NHEJ and HR, we used an in vivo assay that measures the repair of an induced chromosomal break. The reporter cassette for detection of NHEJ previously ...

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“…Telomeres are protected by shelterin, a protein complex of six subunits, including telomere repeat-binding factors 1 (TRF1) and 2 (TRF2), protection of telomeres protein 1 (POT1), TRF1-interacting protein 2 (TIN2), tripeptidyl peptidase 1 (TPP1), and repressor/activator site-binding protein 1 (RAP1) (20)(21)(22)(23)(24). TRF2 serves as an anchoring molecule to facilitate the formation of telomeric cap-like structures, thereby preventing the ends of chromosomes from aberrant DNA recombination and degradation (20,23,24). Encoded by10 exons, TRF2 consists of a C-terminal telomere-binding Myb domain and an N-terminal dimerization domain ( Fig.…”

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Nontelomeric splice variant of telomere repeat-binding factor 2 maintains neuronal traits by sequestering repressor element 1-silencing transcription factor

Zhang

Casaday-Potts²,

Precht³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Telomere repeat-binding factor 2 (TRF2) is critical for telomere integrity in dividing stem and somatic cells, but its role in postmitotic neurons is unknown. Apart from protecting telomeres, nuclear TRF2 interacts with the master neuronal gene-silencer repressor element 1-silencing transcription factor (REST), and disruption of this interaction induces neuronal differentiation. Here we report a developmental switch from the expression of TRF2 in proliferating neural progenitor cells to expression of a unique short nontelomeric isoform of TRF2 (TRF2-S) as neurons establish a fully differentiated state. Unlike nuclear TRF2, which enhances REST-mediated gene repression, TRF2-S is located in the cytoplasm where it sequesters REST, thereby maintaining the expression of neuronal genes, including those encoding glutamate receptors, cell adhesion, and neurofilament proteins. In neurons, TRF2-S-mediated antagonism of REST nuclear activity is greatly attenuated by either overexpression of TRF2 or administration of the excitatory amino acid kainic acid. Overexpression of TRF2-S rescues kainic acid-induced REST nuclear accumulation and its gene-silencing effects. Thus, TRF2-S acts as part of a unique developmentally regulated molecular switch that plays critical roles in the maintenance and plasticity of neurons. . REST binds to a conserved 23-bp motif, repressor element 1 (RE1), of numerous neuronal genes (8, 9). During the early stages of neurogenesis, REST is greatly reduced by ubiquitin/proteasome degradation, resulting in derepression of genetic program for the neuronal phenotype (1, 2). Although it is unclear whether REST is present and functional in postmitotic neurons, emerging evidence suggests that REST dysfunction in adult neurons contributes to several neurological disorders, including cerebral ischemia (10) and epilepsy (11-13). In addition, Zuccato and colleagues demonstrated that a wild-type huntingtin protein inhibits the repressive effect of REST by sequestering it in the cytoplasm, whereas mutant huntingtin causes an aberrant nuclear accumulation of REST (14,15). Because huntingtin is also expressed in nonneuronal cells, there is an ongoing search for factors that may regulate the functionality of REST, particularly in mature neurons in the adult brain (4, 16).Alternative pre-mRNA splicing is a major contributor to proteomic diversity during development. From a single pre-mRNA species, multiple mRNA isoforms are generated by the shuffling of exons at intron-exon boundaries (17,18). By containing or excluding certain pre-mRNA sequences, different splicing isoforms of an encoded protein may exhibit distinct subcellular localizations, protein-protein association, and/or enzymatic activities. Recent studies indicate that nearly 95% of human multiexon genes undergo alternative splicing (17). Neurons, in particular, exhibit an unusually large number of functionally relevant alternative splicing events in which specific protein isoforms are produced to regulate a range of neuronal properties, including excitabil...

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DNA damage-induced phosphorylation of the human telomere-associated protein TRF2

Cited by 81 publications

References 44 publications

Controlled light exposure microscopy reveals dynamic telomere microterritories throughout the cell cycle

Controlled light exposure microscopy reveals dynamic telomere microterritories throughout the cell cycle

TRF2 is required for repair of nontelomeric DNA double-strand breaks by homologous recombination

Nontelomeric splice variant of telomere repeat-binding factor 2 maintains neuronal traits by sequestering repressor element 1-silencing transcription factor

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