Sénescence | EPFL Graph Search

En biologie, la sénescence (du senex, « vieil homme » ou « grand âge ») est un processus physiologique qui entraîne une lente dégradation des fonctions de la cellule (notion spécifique de sénescence cellulaire) à l'origine du vieillissement des organismes. Par extension, les biologistes parlent de processus de sénescence des organes et des organismes. La relation entre la sénescence cellulaire et le vieillissement de l'organisme est encore mal comprise. Depuis les années 2000, on sait que la sénescence cellulaire intervient de façon positive dans l'embryogenèse et la réparation tissulaire. Ses effets sur l'oncogenèse sont antagonistes (c'est-à-dire qu'elle constitue un mécanisme naturel de limitation du cancer). Le vieillissement existe pour la plupart des espèces animales et végétales, mais pas pour toutes. De très rares espèces ne manifestent qu'une sénescence négligeable, voire aucun vieillissement observable. Certaines sont même capables d'inverser leur processus de vieillisseme

Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation

Dania Al Labban, Cathrin Brisken, Witold Waldemar Kilarski, Csaba Ferenc László, Elena Menietti, Melody Swartz

Stromal fibroblast senescence has been linked to ageing-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAFs) are frequently increased. Loss or downmodulation of the Notch effector CSL (also known as RBP-Jκ) in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumours. We report that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as a direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is downmodulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas, whereas p53 expression and function are downmodulated only in the latter, with paracrine FGF signalling as the probable culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation-stromal co-evolution model under convergent CSL-p53 control.

Nature Publishing Group2015

Telomeric Repeat Containing RNAs and the Response to Telomere Deprotection in Saccharomyces Cerevisiae

Andrea Bernardo Panza

Telomeres are the DNA/RNA/protein structures at the end of linear eukaryotic chromosomes, which protect them against the DNA damage repair machinery, preventing chromosome end-to-end fusions and aberrant recombination. Moreover, telomeres compensate for the erosion that occurs at every cycle of DNA replication maintaining telomere length through the action of the telomerase reverse transcriptase. Even if telomeres have many features in common with heterochromatic DNA, they have been shown to be transcribed into telomeric repeat-containing RNA (TERRA) both in vertebrates and plants. In the first part of this work we demonstrate that TERRA expression is conserved in the yeast Saccharomyces cerevisiae. Moreover, TERRA is transcribed by RNA polymerase II, it is polyadenylated and its levels in wild type cells are maintained low through the action of the 5’ to 3’ RNA exonuclease Rati. Indeed cells harboring the thermosensitive mutant allele ratl-1 accumulate high levels of TERRA even at semipermissive temperature. Moreover, ratl-1 mutant cells display a telomere shortening phenotype that is rescued by RNase H overexpression, indicating that DNA/RNA hybrids, which can accumulate in this mutant, inhibit the normal telomere maintenance. In the second part of this work we tried to define TERRA function(s) in response to telomere alterations in yeast cells. We observed that TERRA increases during senescence and survivor formation in est2A mutant cells, which undergo through telomere shortening due to telomerase deletion. The observed increase in TERRA does not require the recombination machinery. Moreover, though TERRA levels are not altered by global DNA damage, they are raised in cdcl3-l, stnl-13 and ku70A mutants, which display telomere resection and DNA damage checkpoint activation at restrictive temperature, suggesting a specific role for TERRA in response to telomere alterations. Since the TERRA increase in telomere deprotection-mutants is suppressed by the deletion of either the 5’ to 3’ exonuclease EXOl or one of the checkpoint factors MEC1, TEL1 and RAD9, we suggest that TERRA is part of a specific checkpoint response, which is induced upon telomere resection. Finally, since est2A cells harboring the ratl-1 mutation display a prolonged senescence phenotype, we suspect a role for TERRA in telomere protection and in particular in preventing telomeric recombination.

EPFL2012

Long noncoding RNA SNHG12 integrates a DNA-PK-mediated DNA damage response and vascular senescence

Johan Auwerx, Lei Chen, Norman Lionel Moullan

Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr(-/-) mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr(-/-) mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD(+), fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.

AMER ASSOC ADVANCEMENT SCIENCE2020

Telomeric Repeat Containing RNAs and the Response to Telomere Deprotection in Saccharomyces Cerevisiae

Andrea Bernardo Panza

EPFL2012