SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling

The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.

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The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

Cancers ◽

10.3390/cancers12040949 ◽

2020 ◽

Vol 12 (4) ◽

pp. 949 ◽

Cited By ~ 4

Author(s):

Marta Recagni ◽

Joanna Bidzinska ◽

Nadia Zaffaroni ◽

Marco Folini

Keyword(s):

Cancer Cells ◽

Tumor Biology ◽

Telomerase Activity ◽

Telomere Maintenance ◽

Limited Information ◽

Adaptive Responses ◽

Therapeutic Implications ◽

Telomerase Inhibitors ◽

Alternative Lengthening

Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibitor tested in clinical trials. Conversely, the limited information available on the molecular underpinnings of ALT has hindered thus far the development of genuine ALT-targeting agents. Moreover, whether anti-telomerase therapies may be hampered or not by possible adaptive responses is still debatable. Nonetheless, it is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism. This notion, together with the evidence that both telomere maintenance mechanisms may coexist within the same tumor and may distinctly impinge on patients’ outcomes, suggests that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated.

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Fission Yeast Taz1 and RPA Are Synergistically Required to Prevent Rapid Telomere Loss

Molecular Biology of the Cell ◽

10.1091/mbc.e06-12-1084 ◽

2007 ◽

Vol 18 (6) ◽

pp. 2378-2387 ◽

Cited By ~ 33

Author(s):

Tatsuya Kibe ◽

Yuuki Ono ◽

Koichiro Sato ◽

Masaru Ueno

Keyword(s):

Fission Yeast ◽

Binding Protein ◽

Protein A ◽

Telomere Maintenance ◽

Helicase Domain ◽

Recq Helicase ◽

Telomeric Dna ◽

Telomere Binding Protein ◽

Recombination Repair ◽

Telomere Loss

The telomere complex must allow nucleases and helicases to process chromosome ends to make them substrates for telomerase, while preventing these same activities from disrupting chromosome end-protection. Replication protein A (RPA) binds to single-stranded DNA and is required for DNA replication, recombination, repair, and telomere maintenance. In fission yeast, the telomere binding protein Taz1 protects telomeres and negatively regulates telomerase. Here, we show that taz1-d rad11-D223Y double mutants lose their telomeric DNA, indicating that RPA (Rad11) and Taz1 are synergistically required to prevent telomere loss. Telomere loss in the taz1-d rad11-D223Y double mutants was suppressed by additional mutation of the helicase domain in a RecQ helicase (Rqh1), or by overexpression of Pot1, a single-strand telomere binding protein that is essential for protection of chromosome ends. From our results, we propose that in the absence of Taz1 and functional RPA, Pot1 cannot function properly and the helicase activity of Rqh1 promotes telomere loss. Our results suggest that controlling the activity of Rqh1 at telomeres is critical for the prevention of genomic instability.

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The Role of Cold Inducible RNA-Binding Protein in Cardiac Physiology and Diseases

Frontiers in Pharmacology ◽

10.3389/fphar.2021.610792 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peng Zhong ◽

Jianye Peng ◽

Zhouyan Bian ◽

He Huang

Keyword(s):

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Stress Conditions ◽

Telomere Maintenance ◽

Transcriptional Level ◽

Cardiac Physiology ◽

Electrophysiological Properties ◽

Kidney Liver

Cold-inducible RNA-binding protein (CIRP) is an intracellular stress-response protein that can respond to various stress conditions by changing its expression and regulating mRNA stability. As an RNA-binding protein, CIRP modulates gene expression at the post-transcriptional level, including those genes involved in DNA repair, cellular redox metabolism, circadian rhythms, telomere maintenance, and cell survival. CIRP is expressed in a large variety of tissues, including testis, brain, lung, kidney, liver, stomach, bone marrow, and heart. Recent studies have observed the important role of CIRP in cardiac physiology and diseases. CIRP regulates cardiac electrophysiological properties such as the repolarization of cardiomyocytes, the susceptibility of atrial fibrillation, and the function of the sinoatrial node in response to stress. CIRP has also been suggested to protect cardiomyocytes from apoptosis under various stress conditions, including heart failure, high glucose conditions, as well as during extended heart preservation under hypothermic conditions. This review summarizes the findings of CIRP investigations in cardiac physiology and diseases and the underlying molecular mechanism.

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Notch Signaling Regulation in Autoinflammatory Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21228847 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8847

Author(s):

Rossella Gratton ◽

Paola Maura Tricarico ◽

Adamo Pio d'Adamo ◽

Anna Monica Bianco ◽

Ronald Moura ◽

...

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Target Genes ◽

Notch Pathway ◽

Autoinflammatory Diseases ◽

Cellular Processes ◽

Core Components

Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.

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TPP1 Regulates hTERT Expression and Predicts Early Malignant Event and Prognosis of Cervical Cancer

10.21203/rs.3.rs-794147/v1 ◽

2021 ◽

Author(s):

Qiaoli Wang ◽

Caifeng Gong ◽

Hui Yang ◽

Fuxiang Zhou ◽

Qiuji Wu ◽

...

Keyword(s):

Cervical Cancer ◽

Protein Expression ◽

Binding Protein ◽

High Expression ◽

Cancer Development ◽

Htert Expression ◽

Telomere Binding Protein ◽

Normal Cervix ◽

Cervical Cancer Development

Abstract Background: Cervical cancer is one of the most common deadly cancer in women worldwide. However, identifying specific biomarkers is still needed. Telomere-binding protein 1 (TPP1) is vital to telomerase activity. However, the role of TPP1 in cervical cancer and its association with human telomerase reverse transcriptase (hTERT) is unclear.This study aimed at exploring the role of telomere-binding protein 1 (TPP1) in cervical cancer development and progression, and potential mechanisms.Methods: Tissue samples from a total of 274 participants were enrolled for the evaluation of protein expression,156 of whom diagnosed withcervical cancers, 102 with cervical intraepithelial neoplasia (CIN) and 16 with normal cervix. In addition, in vitro cellular models with cervical cancer cell lines Hela, Siha, and C33a were transfected by TPP1-siRNAand protein expression of TPP1 and hTERT were assessed. Results: Compared with normal cervix, TPP1 expression was significantly higher in CIN-III and cervical cancers (P<0.001 for both). High expression of TPP1alone (Plog-rank=0.047)andhigh co-expression of TPP1/hTERT (Plog-rank=0.005)weresignificantly associated with worse survival of cervical cancer patients.After adjusting for well-known prognosis factors, hazard ratio was 2.03(95% confidence interval [CI] 0.99-4.16)for high expression of TPP1 and 2.01(95% CI 1.10-3.67) for high co-expression of TPP1/hTERT. TPP1 and hTERT expressions were positively correlated atall levels of cervical lesions (r=0.524, P<0.001). Knockdown of TPP1 decreased hTERT mRNA and protein expression.Conclusions: High expression of TPP1 might be an early event during cervical cancer development and could be served as apotential prognosis biomarker, especially when used together with hTERT. TPP1 might regulate hTERT expression with detailed underlying mechanisms warrant further investigation.

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Abstract 307: Apoa-1 Binding Protein Regulates Retinal Angiogenesis via Control of Notch Signaling

Circulation Research ◽

10.1161/res.119.suppl_1.307 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Renfang Mao ◽

Yury Miller ◽

Longhou Fang

Keyword(s):

Notch Signaling ◽

Cholesterol Metabolism ◽

Binding Protein ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Vital Role ◽

Wild Type ◽

Protein Levels ◽

Secretase Activity

ApoA-1 binding protein (AIBP), a mediator of cholesterol efflux from endothelia cells to HDL, plays a vital role in zebrafish angiogenesis. Although it is evolutionary conserved from Drosophila to human, its role of angiogenesis in higher vertebrate has not been studied. Thus, we propose that the role of AIBP in angiogenesis is also conserved from zebrafish to mice to humans. Mouse models display tremendous power in the study of human cardiovascular disease as the murine and human vasculatures are highly similar. We therefore generated Aibp -/- mice, which are viable and fertile. We then compared retinal vasculature development in Aibp -/- mice and wild-type control mice by whole mount immunostaining. Our data show that AIBP deficiency in mice results in significantly enhanced angiogenesis, including an increase in the radial extension of vascular plexus, the development of a denser upper capillary layer, and more tip cells as well as filopodia in the retinas. Notch signaling pathway plays an essential role for proper angiogenesis. However, the role of cholesterol metabolism in the Notch pathway is poorly understood. We found the expressions of the Notch downstream targets Hes1, Hey1 and Hey2 were upregulated in Aibp -/- retinas compared to controls. Furthermore, the protein level of Notch intracellular domain (NICD) was decreased in Aibp -/- retinas. These results suggest that the activity of Notch signaling is decreased in retinas from Aibp -/- mice. Mechanistically, we found AIBP positively regulates Notch signaling by affect on γ-secretase activity. Moreover, we performed Matrigel plug assay. Comparing that of wild-type, Matrigel plugs from Aibp -/- mice has more VE-cadherin staining and higher VE-cadherin mRNA expression level; and shows lower Hey1 expression as well as decreased NICD protein levels. It indicates that Matrigel plugs from Aibp -/- mice expresses more blood vessels and show lower Notch signaling activity. Our study demonstrated that AIBP inhibits angiogenesis by activating the Notch pathway and are the first to connect AIBP, a cholesterol metabolism regulator, to Notch signaling.

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Abstract LB-084: A role of long interspersed nuclear element-1 (LINE-1) for telomere maintenance in cells with alternative lengthening of telomeres

10.1158/1538-7445.am2015-lb-084 ◽

2015 ◽

Author(s):

Thomas Aschacher ◽

Brigitte Wolf ◽

Philip Kienzl ◽

Florian Enzmann ◽

Barbara Messner ◽

...

Keyword(s):

Telomere Maintenance ◽

Alternative Lengthening Of Telomeres ◽

Alternative Lengthening ◽

Long Interspersed Nuclear Element ◽

In Cells

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The role of recombination in telomere length maintenance

Biochemical Society Transactions ◽

10.1042/bst0370589 ◽

2009 ◽

Vol 37 (3) ◽

pp. 589-595 ◽

Cited By ~ 16

Author(s):

Nicola J. Royle ◽

Aarón Méndez-Bermúdez ◽

Athanasia Gravani ◽

Clara Novo ◽

Jenny Foxon ◽

...

Keyword(s):

Cell Division ◽

Telomere Length ◽

Genome Instability ◽

Nijmegen Breakage Syndrome ◽

Dna Helicase ◽

Telomere Maintenance ◽

Alternative Lengthening ◽

Pathway Activation

Human telomeres shorten during each cell division, predominantly because of incomplete DNA replication. This eventually results in short uncapped telomeres that elicit a DNA-damage response, leading to cellular senescence. However, evasion of senescence results in continued cell division and telomere erosion ultimately results in genome instability. In the long term, this genome instability is not sustainable, and cancer cells activate a TMM (telomere maintenance mechanism), either expression of telomerase or activation of the ALT (alternative lengthening of telomeres) pathway. Activation of the ALT mechanism results in deregulation of recombination-based activities at telomeres. Thus ALT+ cells show elevated T-SCE (telomere sister-chromatid exchange), misprocessing of t-loops that cap chromosomes and recombination-based processes between telomeres or between telomeres and ECTRs (extrachromosomal telomeric repeats). Some or all of these processes underlie the chaotic telomere length maintenance that allows cells in ALT+ tumours unlimited replicative capacity. ALT activation is also associated with destabilization of a minisatellite, MS32. The connection between the minisatellite instability and the deregulation of recombination-based activity at telomeres is not understood, but analysis of the minisatellite can be used as a marker for ALT. It is known that telomere length maintenance in ALT+ cells is dependent on the MRN [MRE11 (meiotic recombination 11)–Rad50–NBS1 (Nijmegen breakage syndrome 1)] complex, but knowledge of the role of other genes, including the Werner's (WRN) and Bloom's (BLM) syndrome DNA helicase genes, is still limited.

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