Many ways to telomere dysfunction: in vivo studies using mouse models

Goytisolo, Fermín A.; Blasco, Marı́a A.

doi:10.1038/sj.onc.1205085

Cited by 92 publications

(68 citation statements)

References 106 publications

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“…Critically short telomeres elicit a DDR provoking entry into cell cycle arrest/senescence or apoptosis (1)(2)(3)(4)(5)(6)(7)(8)(9). To test whether reactivation of the K5TRF2 transgene in K5TRF2/Terc Ϫ/Ϫ females resulted in increased DNA damage signaling at dysfunctional telomeres, we quantified the abundance of ␥H2AX foci in the skin of experimental mice.…”

Section: Resultsmentioning

confidence: 99%

“…D ysfunctional, critically short telomeres elicit a DNA damage response (DDR) that triggers senescence or apoptosis in mammalian cells, two processes that are associated with organismal aging (1)(2)(3)(4)(5)(6)(7)(8)(9). Mice with a targeted deletion of the RNA component of telomerase (Terc Ϫ/Ϫ ) display accelerated telomere shortening, premature loss of tissue renewal, and decreased longevity (3,(7)(8)(9).…”

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confidence: 99%

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Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

Schoeftner

Blanco

Silanes

et al. 2009

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

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Telomeres are heterochromatic structures at chromosome ends essential for chromosomal stability. Telomere shortening and the accumulation of dysfunctional telomeres are associated with organismal aging. Using telomerase-deficient TRF2-overexpressing mice (K5TRF2/Terc ؊/؊ ) as a model for accelerated aging, we show that telomere shortening is paralleled by a gradual deregulation of the mammalian transcriptome leading to cumulative changes in a defined set of genes, including up-regulation of the mTOR and Akt survival pathways and down-regulation of cell cycle and DNA repair pathways. Increased DNA damage from dysfunctional telomeres leads to reduced deposition of H3K27me3 onto the inactive X chromosome (Xi), impaired association of the Xi with telomeric transcript accumulations (Tacs), and reactivation of an X chromosome-linked K5TRF2 transgene that is subjected to X-chromosome inactivation in female mice with sufficiently long telomeres. Exogenously induced DNA damage also disrupts Xi-Tacs, suggesting DNA damage at the origin of these alterations. Collectively, these findings suggest that critically short telomeres activate a persistent DNA damage response that alters gene expression programs in a nonstochastic manner toward cell cycle arrest and activation of survival pathways, as well as impacts the maintenance of epigenetic memory and nuclear organization, thereby contributing to organismal aging.aging ͉ chromosome X inactivation ͉ DNA damage ͉ epigenetics ͉ telomeres D ysfunctional, critically short telomeres elicit a DNA damage response (DDR) that triggers senescence or apoptosis in mammalian cells, two processes that are associated with organismal aging (1-9). Mice with a targeted deletion of the RNA component of telomerase (Terc Ϫ/Ϫ ) display accelerated telomere shortening, premature loss of tissue renewal, and decreased longevity (3,(7)(8)(9). DNA damage signals originating from critically short telomeres in these mice is in line with current models proposing a causative role for DNA damage in organismal aging (10-13). Interestingly, epigenetic alterations at heterochromatic regions are proposed to lead to changes in gene expression associated with aging (14-16). In S. cerevisiae, induction of DNA double-strand breaks (DSBs) or cellular stress causes a dramatic redistribution of telomeric silent information regulator (Sir) proteins and yKU proteins (17-19), thus linking changes in telomere chromatin to global epigenetic alterations. Sir complex relocalization is known to alter the expression of stress response genes, survival factors, and ribosomal biogenesis (20,21). In functional analogy to yeast, mammalian SIRT1 is redistributed upon induction of DNA damage, causing broad alterations in global gene expression (22). Collectively, these findings suggest that agingrelated DNA damage drives gene expression alterations that could promote the development of aging pathologies.An important question to determine is how the various types of DNA damage impact gene expression changes associated with organismal a...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

Schoeftner

Blanco

Silanes

et al. 2009

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

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“…Furthermore, telomere length is but one of many determinants of telomere function. The function of telomere-associated proteins (ie Ku, DNA-PKcs, p53 and many others), 74 many of which are also involved in DNA repair (ie response to radio and chemotherapy), will also be crucial to understand the telomere phenotype of children treated with chemotherapy.…”

Section: Leukemiamentioning

confidence: 99%

Telomere dynamics in childhood leukemia and solid tumors: a follow-up study

et al. 2003

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Telomeres of hematopoietic cells shorten with age, possibly contributing to the aging-associated hematopoietic pathology (immunosenescence, malignant transformation). Accelerated telomere shortening is seen with replicative stress, such as during administration of serial chemotherapy cycles for the treatment of childhood cancer. To define the long-term consequences of pediatric cancer treatment on hematopoietic cell telomere length, we undertook a prospective 4-year follow-up study of a 61-patient cohort of pediatric malignancies in a community-based setting. We found that mononuclear cells (MNC) and granulocytes of children with standard-risk acute lymphoblastic leukemia (ALL) suffered minimal telomere shortening throughout therapy (less than 1 kbp; average follow-up, 20 months), while those of children with solid tumors showed greater and more heterogenous telomere attrition (0.5-2.8 kbp, average follow-up, 9 months). In addition, we evaluated the role of telomerase, the enzyme commonly up-regulated in pediatric leukemic and solid tumor cells for telomere length maintenance, as a disease marker. Serial determinations of telomerase in MNC were useful to confirm disease remission in leukemia, but play no role in the follow-up of children with solid tumors.

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“…Most somatic cells do not express sufficient telomerase to compensate for the loss of telomere repeats during cell division, something that eventually results in critical telomere shortening and loss of chromosome capping. Short or uncapped telomeres activate DNA damage signaling pathways and are processed by DNA repair pathways leading to end-toend fusions and loss of cell viability (Goytisolo and Blasco, 2002). In contrast to somatic cells, cancer cells acquire immortality by reactivating telomerase, which allows them to maintain telomeres above a minimumlength threshold (Shay and Wright, 2002).…”

Section: Introductionmentioning

confidence: 99%

Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling

et al. 2006

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Here, we show that ectopic expression of the catalytic subunit of mouse telomerase (mTert) confers a growth advantage to primary murine embryonic fibroblasts (MEFs), which have very long telomeres, as well as facilitates their spontaneous immortalization and increases their colony-forming capacity upon activation of oncogenes. We demonstrate that these telomere lengthindependent growth-promoting effects of mTert overexpression require catalytically active mTert, as well as the formation of mTert/Terc complexes. The gene expression profile of mTert-overexpressing MEFs indicates that telomerase enhances growth in these cells through the repression of growth-inhibiting genes of the transforming growth factor-beta (TGF-b) signaling network. We functionally validate this result by showing that mTert abrogates the growth-inhibitory effect of TGF-b in MEFs, thus demonstrating that telomerase increments the proliferative potential of primary mouse embryonic fibroblasts by targeting the TGF-b pathway.

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Many ways to telomere dysfunction: in vivo studies using mouse models

Cited by 92 publications

References 106 publications

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

Telomere dynamics in childhood leukemia and solid tumors: a follow-up study

Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling

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