Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation

Fumagalli, Marzia; Rossiello, Francesca; Clerici, Michela; Barozzi, Sara; Cittaro, Davide; Kaplunov, Jessica; Bucci, Gabriele; Dobreva, Miryana; Matti, Valentina; Beauséjour, Christian; Herbig, Utz; Longhese, Maria Pia; Fagagna, Fabrizio d’Adda di

doi:10.1038/ncb2466

Cited by 694 publications

(701 citation statements)

References 55 publications

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“…However, since not all cells with DDR foci expressed high levels of α‐SMA in stress fibers (Supporting Information Figure S3d), our data also suggested that activation of the DDR alone is not sufficient for myofibroblast transdifferentiation and that other factors, such as timing of DDR induction or long‐term persistence of the DDR, are critical for activating the transdifferentiation program. As dysfunctional telomeres activate a persistent DDR while nontelomeric DSBs are repaired within minutes of being generated (Fumagalli et al, 2012; Hewitt et al, 2012), we tested whether fibroblasts are stimulated to transdifferentiate preferentially due to a persistent telomeric DDR. By simultaneously immunostaining TGF‐β1‐treated cells for α‐SMA expression and TIF formation, we discovered that the great majority of α‐SMA‐expressing myofibroblasts indeed displayed dysfunctional telomeres and were TIF positive (75%).…”

Section: Resultsmentioning

confidence: 99%

“…Significantly, telomere dysfunction‐induced senescence (TDIS) can also be triggered in the absence of continuous cell proliferation and in the absence of critical telomere shortening. For example, genotoxic stresses that cause DSB formation in telomeric repeats can rapidly activate TDIS, as telomeric breaks resist DNA repair activities (Fumagalli et al, 2012; Hewitt et al, 2012; Suram et al, 2012). Stresses that have been demonstrated to cause TDIS include oncogene expression (Patel, Suram, Mirani, Bischof, & Herbig, 2016; Suram et al, 2012), DNA replication stress (Boccardi et al, 2015; Fumagalli et al, 2012; Hewitt et al, 2012), and reactive oxygen species (ROS) (Boccardi et al, 2015), among others.…”

Section: Introductionmentioning

confidence: 99%

“…For example, genotoxic stresses that cause DSB formation in telomeric repeats can rapidly activate TDIS, as telomeric breaks resist DNA repair activities (Fumagalli et al, 2012; Hewitt et al, 2012; Suram et al, 2012). Stresses that have been demonstrated to cause TDIS include oncogene expression (Patel, Suram, Mirani, Bischof, & Herbig, 2016; Suram et al, 2012), DNA replication stress (Boccardi et al, 2015; Fumagalli et al, 2012; Hewitt et al, 2012), and reactive oxygen species (ROS) (Boccardi et al, 2015), among others. Whether generated due to progressive telomere erosion or due to DSB formation in telomeric repeats, telomere dysfunction activates a persistent DDR that is mediated by and dependent on p53, a transcription factor that not only trans‐activates DDR genes (Molchadsky, Rivlin, Brosh, Rotter, & Sarig, 2010), but also regulates a wide range of other biological activities including cell differentiation (Rivlin, Koifman, & Rotter, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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Cells that had undergone telomere dysfunction‐induced senescence secrete numerous cytokines and other molecules, collectively called the senescence‐associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF‐β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS‐dependent manner. Surprisingly, instead of activating cellular senescence, TGF‐β1‐induced telomere dysfunction caused fibroblasts to transdifferentiate into α‐SMA‐expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF‐β1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF‐β1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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“…Although most DSBs in arrested cells are eventually resolved by cellular DSB repair processes, some persist and consequently convert the otherwise transient DDR into a more permanent growth arrest. We and others have demonstrated that the persistent DDR is primarily telomeric, triggered by irreparable telomeric DSBs (1,10,11).…”

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confidence: 99%

Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

Patel

Anitha

Mirani

et al. 2016

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

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Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc-dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.oncogene-induced senescence | telomerase | telomere | senescence escape |

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“…The main mediators of DNA damage response are the DNA damage kinases ATM, ATR, CHK1, and CHK2, which phosphorylate and activate several cell cycle proteins, including p53 (Campisi and d'Adda di Fagagna 2007). Moreover, phosphorylated p53 protein activates the expression of p21, which binds to and inhibits some CDKcyclin complexes, particularly those involving CDK2, finally altering the proliferative activity of cells (Fumagalli et al 2012). Both cell proliferation and differentiation are striking features of the new tissue formation phase, and several markers and morphologic features characterize senescent cells.…”

Section: Cell Proliferationmentioning

confidence: 99%

Gingival Wound Healing

Cáceres

Martínez

et al. 2014

J Dent Res

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Gingival wound healing comprises a series of sequential responses that allow the closure of breaches in the masticatory mucosa. This process is of critical importance to prevent the invasion of microbes or other agents into tissues, avoiding the establishment of a chronic infection. Wound healing may also play an important role during cell and tissue reaction to long-term injury, as it may occur during inflammatory responses and cancer. Recent experimental data have shown that gingival wound healing is severely affected by the aging process. These defects may alter distinct phases of the wound-healing process, including epithelial migration, granulation tissue formation, and tissue remodeling. The cellular and molecular defects that may explain these deficiencies include several biological responses such as an increased inflammatory response, altered integrin signaling, reduced growth factor activity, decreased cell proliferation, diminished angiogenesis, reduced collagen synthesis, augmented collagen remodeling, and deterioration of the proliferative and differentiation potential of stem cells. In this review, we explore the cellular and molecular basis of these defects and their possible clinical implications.

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Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation

Cited by 694 publications

References 55 publications

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

Gingival Wound Healing

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