Shortened telomeres join to DNA breaks interfering with their correct repair

Latre, Laura; Tusell, Laura; Martı́n, Marga; Miró, Rosa; Egozcue, J.; Blasco, Marı́a A.; Genescà, Anna

doi:10.1016/s0014-4827(03)00134-4

Cited by 67 publications

(40 citation statements)

References 15 publications

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“…Thus, the nearly blunt-ended double-strand breaks induced by C-1027 at its preferred cleavage site within the telomere repeat may be refractory to repair and may cause shortening or even a complete loss of telomere DNA. 8 DNA ligase IV-dependent NHEJ can fuse chromosomes with shortened telomeres to double-strand breaks located elsewhere in the genome (28), leading to chromosome instability (49). In the present study, such incorrect misrejoining was observed after treatment with as low as 0.035 nmol/L C-1027 (see Fig.…”

Section: Resultssupporting

confidence: 53%

The Antitumor Enediyne C-1027 Alters Cell Cycle Progression and Induces Chromosomal Aberrations and Telomere Dysfunction

McHugh

Gawron²,

Matsui³

et al. 2005

Cancer Research

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Section: Resultssupporting

confidence: 53%

The Antitumor Enediyne C-1027 Alters Cell Cycle Progression and Induces Chromosomal Aberrations and Telomere Dysfunction

McHugh

Gawron²,

Matsui³

et al. 2005

Cancer Research

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“…In the mouse, the most frequent type of end-to-end fusion associated with telomere dysfunction is RLF (7,17). In addition, it has recently been shown that loss of telomere capping interferes with proper repair of DNA double-strand breaks (DSB) in the genome, as indicated by the fact that telomerase-deficient mice with critically short or uncapped telomeres are hypersensitive to ionizing radiation (IR) (18,22,32). In particular, critically short telomeres in these mice illegitimately join to IR-induced DSB in the genome, thus increasing chromosomal instability (22).…”

Section: Targeted Expression Of Tert To the Thymus: Lck-tert Micementioning

confidence: 99%

“…In addition, it has recently been shown that loss of telomere capping interferes with proper repair of DNA double-strand breaks (DSB) in the genome, as indicated by the fact that telomerase-deficient mice with critically short or uncapped telomeres are hypersensitive to ionizing radiation (IR) (18,22,32). In particular, critically short telomeres in these mice illegitimately join to IR-induced DSB in the genome, thus increasing chromosomal instability (22). Furthermore, there has been recent speculation that Tert overexpression may directly interfere with proper DNA repair of lesions in the genome in a way that is independent of telomere capping (5).…”

Section: Targeted Expression Of Tert To the Thymus: Lck-tert Micementioning

confidence: 99%

Constitutive Expression of Tert in Thymocytes Leads to Increased Incidence and Dissemination of T-Cell Lymphoma in Lck-Tert Mice

Canela

Juan

Flores

et al. 2004

Molecular and Cellular Biology

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Here we describe a new mouse model with constitutive expression of the catalytic subunit of telomerase (Tert) targeted to thymocytes and peripheral T cells (Lck-Tert mice). Two independent Lck-Tert mouse lines showed higher incidences of spontaneous T-cell lymphoma than the corresponding age-matched wild-type controls, indicating that constitutive expression of Tert promotes lymphoma. Interestingly, T-cell lymphomas in Lck-Tert mice were more disseminated than those in wild-type controls and affected both lymphoid and nonlymphoid tissues, while nonlymphoid tissues were never affected with lymphoma in age-matched wild-type controls. Importantly, these roles of Tert constitutive expression in promoting tumor progression and dissemination were independent of the role of telomerase in telomere length maintenance, since telomere length distributions on a single-cell basis were identical in Lck-Tert and wild-type thymocytes. Finally, Tert constitutive expression did not interfere with telomere capping in Lck-Tert primary thymocytes, although it resulted in greater chromosomal instability upon gamma irradiation in Lck-Tert primary lymphocytes than in controls, suggesting that Tert overexpression may interfere with the cellular response to DNA damage.Telomerase activity can provide limitless proliferative capacity, a hallmark of human cancer, through its ability to elongate telomeres (2). The majority of human tumors activate telomerase at some point during their development (27). The role of telomerase in tumor cells has been assumed to be restricted to preventing TTAGGG exhaustion from chromosome ends, which otherwise would trigger cell arrest and/or apoptosis (2). More recently, however, forced telomerase expression in cells and mice with sufficiently long telomeres has shown that telomerase can also promote growth and survival in a manner which appears to be uncoupled from net telomere lengthening (5). Mounting evidence for this novel role of telomerase in tumorigenesis has been obtained from studying mouse models. Telomerase activity is upregulated during mouse tumorigenesis, despite the fact that mice have very long telomeres (3, 9). In addition, mice that overexpress the catalytic component of mouse telomerase under the control of a keratin 5 promoter (K5-Tert mice) are more susceptible to developing both carcinogen-induced and spontaneous tumors (14, 16). Mice with transgenic telomerase expression under the control of a ␤-actin constitutive promoter also have an increased incidence of spontaneous tumors as they age (1). These findings suggest that constitutive transgenic telomerase expression promotes tumorigenesis in mice with very long telomeres. However, the mechanisms by which constitutive expression of the catalytic subunit of telomerase (Tert) promotes tumorigenesis independently of telomere length remain unknown.Here we describe the generation of a new mouse model with Tert constitutive expression specifically targeted to the thymus by use of the Lck promoter (Lck-Tert mice). We show here that these mice ...

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“…La pérdida de la función de protección de los telómeros debido al acortamiento hace que los cromosomas sean susceptibles de fusionarse con otros extremos de cromosomas y que se produzcan roturas de ADN doble cadena, lo cual resulta en reordenamientos cromosómicos que pueden afectar la estabilidad genómi-ca (18). Los telómeros cortos pierden sus marcas epigenéticas y son propensos a recombinaciones (19).…”

Section: Introductionunclassified

Telómeros Y Calidad De La Dieta: Una Revision Sistematica

Marti¹,

Echeverría

Morell‐Azanza

et al. 2017

Nutr Hosp

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Palabras clave:Telómeros. Dieta mediterránea. Estrés oxidative. ADN. ResumenFundamento: existen pocos estudios que hayan evaluado la relación entre la calidad de la dieta y la integridad telómerica en humanos. Los telómeros son regiones de ADN no codificante que se encuentran en los extremos de los cromosomas, cuya longitud además de indicar la esperanza de vida, indica el estado global de salud. El objetivo de la presente revisión sistemática es recopilar la evidencia existente sobre la relación entre la longitud de los telómeros y la calidad de la dieta para conocer el impacto que algunos nutrientes, alimentos y patrones dietéticos pueden tener sobre la homeostasis telomérica y por lo tanto, sobre la salud en general. Material y métodos: se realizó una revisión bibliográfica en la base de datos PubMed para identificar los artículos publicados (en inglés o español) hasta diciembre de 2016 que cumplían los siguientes criterios: incluían sujetos humanos; eran estudios transversales; estudios de casos y controles; estudios de cohortes prospectivos o estudios de intervención; que evaluaban la relación de los nutrientes, alimentos o patrones dietéticos con la longitud de los telómeros. La estrategia de búsqueda incluía las siguientes palabras clave: nutrients or food OR food groups OR diet OR dietary pattern OR eating pattern OR dietary habits OR diet type AND telomere attrition OR telomere length. En total, se incluyeron 19 estudios transversales, cinco estudios de casos y controles, cinco estudios de cohortes prospectivos y dos estudios de intervención, incluyendo aquellos artículos que se encontraron por listas de referencias de otras publicaciones. Resultados: se encontraron asociaciones positivas entre la longitud de los telómeros y la adherencia a la dieta mediterránea y el consumo de verduras y frutas. Los resultados obtenidos para otros nutrientes, alimentos o patrones dietéticos fueron incoherentes, aunque parece que las carnes procesadas, los cereales, el alcohol y las bebidas endulzadas podrían estar asociados con telómeros más cortos. Conclusiones: la intervención dietética, y en particular la promoción de una dieta de estilo mediterráneo, podría desempeñar un papel en la protección de la integridad telomérica. Key words:Telomere. Mediterranean diet. Oxidative stress. DNA. AbstractBackground: Few studies have evaluated the relationship between diet quality and telomere integrity in humans. Telomeres are regions of non-coding DNA localized at the end of each chromosome whose length, in addition to indicating life expectancy, indicates an overall health status. The objective of this systematic review is to compile the existing evidence on the relationship between telomere length and diet quality to further explore the impact that some nutrients, foods and dietary patterns may have on telomere homeostasis and therefore, in precision nutrition strategies. Material and methods: A bibliographic review was performed in the PubMed database to identify published articles (in English or Spanish) until December 201...

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Shortened telomeres join to DNA breaks interfering with their correct repair

Cited by 67 publications

References 15 publications

The Antitumor Enediyne C-1027 Alters Cell Cycle Progression and Induces Chromosomal Aberrations and Telomere Dysfunction

The Antitumor Enediyne C-1027 Alters Cell Cycle Progression and Induces Chromosomal Aberrations and Telomere Dysfunction

Constitutive Expression of Tert in Thymocytes Leads to Increased Incidence and Dissemination of T-Cell Lymphoma in Lck-Tert Mice

Telómeros Y Calidad De La Dieta: Una Revision Sistematica

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