Mammalian Meiotic Telomeres: Protein Composition and Redistribution in Relation to Nuclear Pores

Scherthan, Harry; Jerratsch, Martin; Li, Bibo; Smith, Susan; Hultén, Maj; Lock, Tycho; Lange, Titia de

doi:10.1091/mbc.11.12.4189

Cited by 141 publications

(128 citation statements)

References 89 publications

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“…6). Because telomeric targeting of human tankyrase requires TRF1 binding (6), lack of this binding explains the absence of detectable tankyrase at mouse telomeres (8) and implies that tankyrase does not regulate telomeres in mice as it does in humans.…”

Section: Discussionmentioning

confidence: 99%

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Identification of a Tankyrase-binding Motif Shared by IRAP, TAB182, and Human TRF1 but Not Mouse TRF1

Sbodio

Wen

2002

Journal of Biological Chemistry

145

149

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Tankyrase-1 and -2 are closely related poly(ADP-ribose) polymerases that use an ankyrin-repeat domain to bind diverse proteins, including TRF (telomere-repeat binding factor)-1, IRAP (insulin-responsive aminopeptidase), and TAB182 (182-kDa tankyrase-binding protein). TRF1 binding allows tankyrase to regulate telomere dynamics in human cells, whereas IRAP binding presumably allows tankyrase to regulate the targeting of IRAP. The mechanism by which tankyrase binds to diverse proteins has not been investigated. Herein we describe a novel RXXPDG motif shared by IRAP, TAB182, and human TRF1 that mediates their binding to tankyrases. Interestingly, mouse TRF1 lacks this motif and thus does not bind either tankyrase-1 or -2. Using the ankyrin domain of tankyrase as a bait in a yeast two-hybrid screen, we also found the RXXPDG motif in six candidate tankyrase partners, including the nuclear/mitotic apparatus protein (NuMA). We verified NuMA as an RXXPDG-mediated partner of tankyrase and suggest that this interaction contributes to the known colocalization of tankyrase and NuMA at mitotic spindle poles.

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Section: Discussionmentioning

confidence: 99%

“…Although Golgi and spindle poles alternately contain the bulk of tankyrase-1, a small fraction of tankyrase-1 is targeted to human telomeres through TRF1 binding (1,6). For yet-unclear reasons, mouse telomeres do not contain detectable amounts of tankyrase-1 by immunofluorescence analysis (8).…”

mentioning

confidence: 99%

Identification of a Tankyrase-binding Motif Shared by IRAP, TAB182, and Human TRF1 but Not Mouse TRF1

Sbodio

Wen

2002

Journal of Biological Chemistry

145

149

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“…The particular dynamics of the shelterin complex proteins in the ITSs suggests a role in chromatin stabilization and protection during meiosis Both TRF1 and RAP1 proteins are essential in organizing and maintaining the T-loop conformation of the telomeres and also in protecting chromosome ends from DNA damage repair proteins (Zhong et al 1992;Li et al 2000;Scherthan et al 2000). In addition, these proteins could be important for the proper attachment of chromosomes into the nuclear envelope (Scherthan et al 2000;Scherthan 2007).…”

Section: Structural Organization Of Its Chromatin During Meiosismentioning

confidence: 99%

Chromatin Organization and Remodeling of Interstitial Telomeric Sites During Meiosis in the Mongolian Gerbil (Meriones unguiculatus)

et al. 2014

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Telomeric DNA repeats are key features of chromosomes that allow the maintenance of integrity and stability in the telomeres. However, interstitial telomere sites (ITSs) can also be found along the chromosomes, especially near the centromere, where they may appear following chromosomal rearrangements like Robertsonian translocations. There is no defined role for ITSs, but they are linked to DNA damage-prone sites. We were interested in studying the structural organization of ITSs during meiosis, a kind of cell division in which programmed DNA damage events and noticeable chromatin reorganizations occur. Here we describe the presence of highly amplified ITSs in the pericentromeric region of Mongolian gerbil (Meriones unguiculatus) chromosomes. During meiosis, ITSs show a different chromatin conformation than DNA repeats at telomeres, appearing more extended and accumulating heterochromatin markers. Interestingly, ITSs also recruit the telomeric proteins RAP1 and TRF1, but in a stage-dependent manner, appearing mainly at late prophase I stages. We did not find a specific accumulation of DNA repair factors to the ITSs, such as gH2AX or RAD51 at these stages, but we could detect the presence of MLH1, a marker for reciprocal recombination. However, contrary to previous reports, we did not find a specific accumulation of crossovers at ITSs. Intriguingly, some centromeric regions of metacentric chromosomes may bind the nuclear envelope through the association to SUN1 protein, a feature usually performed by telomeres. Therefore, ITSs present a particular and dynamic chromatin configuration in meiosis, which could be involved in maintaining their genetic stability, but they additionally retain some features of distal telomeres, provided by their capability to associate to telomere-binding proteins.

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“…Cells were extracted at 10 min in 0.25% Triton-X-100 (Sigma) in PBS. Then slides were subjected to anti-g-H2AX-53BP1 immunofluorescent staining using a mouse monoclonal anti g-H2AX antibody (Upstate) at a ratio of 1:500 and a rabbit anti-53BP1 antibody (Acris Antibodies) at a ratio of 1:250 in PBS, 0.1% bovine serum albumin, 0.05% polysorbate-20, and 0.3% fish gelatin (PBTG buffer) (16). The preparations were incubated with the antibody solution at 4°C overnight, followed by three 5-min washes in PBTG at 37°C.…”

Section: G-h2ax and 53bp1 Immunofluorescencementioning

confidence: 99%

In Vivo Formation of γ-H2AX and 53BP1 DNA Repair Foci in Blood Cells After Radioiodine Therapy of Differentiated Thyroid Cancer

Laßmann¹,

Hänscheid²,

Gassen³

et al. 2010

J Nucl Med

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DNA double-strand breaks (DSBs) are critical cellular lesions that can result from ionizing radiation exposure. A marker for DSB formation is the phosphorylated form of the histone H2 variant H2AX . DSBs also attract the damage sensor p53-binding protein 1 (53BP1) to the DSB-containing chromatin, because 53BP1 associates with the DSB-surrounding chromatin. We studied the induction, persistence, and disappearance of radiation-induced g-H2AX and 53BP1 foci after the first 131 I therapy of patients with differentiated thyroid carcinoma, a model for protracted, continuous, internal whole-body irradiation. Methods: Twenty-six patients (7 men, 19 women; mean age 6 SD, 42 6 13 y) underwent posttherapeutic blood dosimetry according to the standard operating procedure of the European Association of Nuclear Medicine, including peripheral blood sampling and external dose rate measurements at 2-144 h after administration of 131 I for thyroid remnant ablation. The mean time curves of dose accumulation and dose rate to the blood were compared with the mean g-H2AX and 53BP1 foci counts over the same period in samples of mononuclear peripheral blood leukocytes. Results: The mean absorbed dose to the blood in 24 patients evaluable for physical dosimetry was 0.31 6 0.10 Gy (minimum, 0.17 Gy; maximum, 0.57 Gy). After 24 h, the mean daily dose increment was less than 0.05 Gy. The excess focus counts per nucleus-that is, nuclear foci in excess of the low background count-peaked at 2 h after radioiodine administration (median excess foci for g-H2AX [n 5 21 patients], 0.227, and for 53BP1 [n 5 19 patients], 0.235) and progressively declined thereafter. Significantly elevated numbers of excess focus counts per nucleus (median excess foci for g-H2AX [n 5 8 patients], 0.054, and for 53BP1 [n 5 6 patients], 0.046) still were present at 120-144 h after therapy. Because the rate of occurrence of radiation-induced focus counts per nucleus per absorbed dose varied considerably among patients, a dose-response relationship could not be established for this series as a whole. The number of excess radiation-induced focus counts per nucleus per absorbed dose rate increased with time, potentially indicating a slower rate of DNA repair or, alternatively, a higher de novo rate of focus formation. The values over time of both radiation-induced DSB markers correlated closely (r 2 5 0.973). Conclusion: Radiation-induced g-H2AX and 53BP1 nuclear foci are useful markers for detecting radiation exposure after radionuclide incorporation, even for absorbed doses to the blood below 20 mGy. Exposure to ionizing radiation causes several lesions in affected cells because of direct ionization or radical attack (1). Among the most critical defects are DNA double-strand breaks (DSBs), which can lead to efficient cell killing or, through erroneous DNA repair, can be a source of stochastic damage, including increased risk of malignant transformation.Once a DSB forms, the cell initiates the DNA damage response, to which the ataxia-telangiectasia-mutated (ATM) protein,...

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Mammalian Meiotic Telomeres: Protein Composition and Redistribution in Relation to Nuclear Pores

Cited by 141 publications

References 89 publications

Identification of a Tankyrase-binding Motif Shared by IRAP, TAB182, and Human TRF1 but Not Mouse TRF1

Identification of a Tankyrase-binding Motif Shared by IRAP, TAB182, and Human TRF1 but Not Mouse TRF1

Chromatin Organization and Remodeling of Interstitial Telomeric Sites During Meiosis in the Mongolian Gerbil (Meriones unguiculatus)

In Vivo Formation of γ-H2AX and 53BP1 DNA Repair Foci in Blood Cells After Radioiodine Therapy of Differentiated Thyroid Cancer

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