Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres

Zhu, Xu-Dong; Küster, Bernhard; Mann, Matthias; Petrini, John H.J.; Lange, Titia de

doi:10.1038/77139

Cited by 548 publications

(415 citation statements)

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“…Despite this concentration constancy we observed a cell cycle dependent relocation for both proteins. Immunostainings have shown that TRF2 and TRF1 are present at the telomeres throughout the cell cycle (21,60). We have now added quantitative data to these observations based on GFP-constructs and single cell analysis.…”

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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“…RAD50, MRE11 and NBS1 are present in TRF2 immunocomplexes (Zhu et al, 2000) via their interaction with RAP1 (O'Connor et al, 2004). RAD50 and MRE11 are located at telomeres throughout interphase, and are joined by NBS1 in S-phase (Zhu et al, 2000). It has been suggested that MRE11 and RAD50 may be required to stabilize telomere (t)-loop formation (which is essentially an unresolved homologous recombination event) throughout most of the cell cycle, and that the transient recruitment of NBS1 in Sphase may be required for access of the DNA replication machinery (Zhu et al, 2000).…”

Section: Screen For Alt Genes W-q Jiang Et Almentioning

confidence: 97%

“…In addition to being present in APBs, the MRN complex has been shown to be associated with telomeres (Zhu et al, 2000). RAD50, MRE11 and NBS1 are present in TRF2 immunocomplexes (Zhu et al, 2000) via their interaction with RAP1 (O'Connor et al, 2004).…”

Section: Screen For Alt Genes W-q Jiang Et Almentioning

confidence: 99%

Section: Screen For Alt Genes W-q Jiang Et Almentioning

confidence: 99%

“…In addition to constitutive components of PML bodies such as PML and Sp100, they also contain other proteins involved in DNA replication, recombination and repair including RAD51, RAD52 and RPA (Yeager et al, 1999), RAD51D (Tarsounas et al, 2004), BLM (Yankiwski et al, 2000;Stavropoulos et al, 2002), WRN (Johnson et al, 2001), RAP1 and BRCA1 (Wu et al, 2003), MRE11, RAD50 and NBS1 (Wu et al, 2000;Zhu et al, 2000), ERCC1 and XPF (Zhu et al, 2003), hRAD1, hRAD9, hRAD17 and hHUS1 (Nabetani et al, 2004), Rif1 (Silverman et al, 2004) and hnRNP A2 (Moran-Jones et al, 2005). Formation of APBs requires NBS1, which recruits MRE11, RAD50 and BRCA1 into these structures (Wu et al, 2003;Jiang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference

et al. 2007

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Telomerase-negative cancer cells can maintain their telomeres by a recombination-mediated alternative lengthening of telomeres (ALT) process. We reported previously that sequestration of MRE11/RAD50/NBS1 complexes represses ALT-mediated telomere length maintenance, and suppresses formation of ALT-associated promyelocytic leukemia (PML) bodies (APBs). APBs are PML bodies containing telomeric DNA and telomere-binding proteins, and are observed only in a small fraction of cells within asynchronously dividing ALT-positive cell populations. Here, we report that methionine restriction caused a reversible arrest in G 0 /G 1 phase of the cell cycle and reversible induction of APB formation in most cells within an ALT-positive population. We combined methionine restriction with RNA interference to test whether the following proteins are required for APB formation: PML body-associated proteins, PML and Sp100; telomereassociated proteins, TRF1, TRF2, TIN2 and RAP1; and DNA repair proteins, MRE11, RAD50, NBS1 and 53BP1. APB formation was not decreased by depletion of Sp100 (as reported previously) or of 53BP1, although 53BP1 partially colocalizes with APBs. Depletion of the other proteins suppressed APB formation. Because of the close linkage between ALT-mediated telomere maintenance and ability to form APBs, the eight proteins identified by this screen as being required for APB formation are also likely to be required for the ALT mechanism.

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TheMre11 Nuclease Complex

Hopfner

Bemeleit

Lammens

2004

Handbook of Metalloproteins

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The repair of DNA double‐strand breaks (DSBs) is necessary to maintain genome stability and prevent cell aberration and cancer development. Meiotic recombination 11 (Mre11) and radiation sensitivity 50 (Rad50) form an evolutionary conserved complex (denoted Mre11 complex) that is a key factor in the detection, repair, and signaling of DSBs. The Mre11 complex possesses ATP‐stimulated DNA binding, DNA endo‐ and exonuclease activities as well as DNA cross‐linking functions. The Mre11 complex is a primary sensor for DNA DSBs and is involved in many aspects of the repair of and cellular response to DNA DSBs. Its activity is controlled by at least three different metal binding sites, a manganese‐dependent nuclease (Mre11 phosphodiesterase domain), a magnesium‐dependent ATPase (Rad50 ABC ATPase domain), and a zinc‐mediated DNA tethering function, located at the apex of a long Rad50 coiled‐coil domain. Although the mechanism remains to be shown, current structural and functional data indicate that the Mre11 complex is an ATP‐dependent cross‐linker and a processing factor for DNA ends.

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Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres

Cited by 548 publications

References 31 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

Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference

TheMre11 Nuclease Complex

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