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Organisation du centromère pendant la sénescence

Year: 2024
Type: dissertation
Abstract: Cellular stresses promote senescence, an irreversible exit from the cell cycle, that in turn promote an inflammatory response. An early event in senescence is the formation of Senescence Associated Distension of Satellite DNA (SADS) where satellite DNA, a type of repetitive DNA, unfold. How SADS originate and what is their role in promoting senescence is unknown. To answer these questions, we study a particular type of repetitive satellite DNA, a-satellite, that is present at chromosomal regions called centromeres. Centromeres are loci essential to mediate accurate sister chromatids segregation during both meiosis and mitosis. Within centromeres, a-satellite DNA folds into unique secondary structures and plays a role in centromere functionality, highlighting the importance of maintaining its architecture.To induce SADS formation I subjected cells to several cellular stresses to induce senescence like DNA damage, aneuploidy or p53 stabilization. By investigating the factors promoting SADS formation and their cellular consequences, I found that SADS occur through p53 activation in a DNA damage independent manner. However, upon DNA damage the presence of p53 become dispensable in promoting SADS formation. Within the DNA damage cascade, I have found that inhibition of the DNA damage response factor ATM minorly prevents SADS formation, but only following DNA damage. Additionally, I discovered that the centromeric proteins CENP-A, CENP-B and CENP-C are important to maintain centromeric DNA compaction in non-cycling cells, with more effect of CENP-B. Importantly, ectopic CENP-B once bound to centromeric DNA partially delay SADS formation and minorly impact the downstream senescence phenotype. This highlights a direct connection between SADS and other senescence phenotypes.Centromeres have unique epigenetic landscape. I have found that during senescence onset centromeres undergo to histone modifications and such epigenetic modifications might influence centromere compaction. I am currently looking into the chromatin accessibility at SADS by measuring histones abundancy and changes of DNA methylation, known to drive important physiological functions like transcription. Here, I found that centromeric transcription is altered during senescence, but this is differently regulated depending on different senescence conditions. This suggest that that while SADS is an early universal hallmark of senescence their outcome might be context driven phenomenon.To this end, I am looking if SADS can influence other senescence hallmarks like SASP. Senescence Associated Secretory Phenotype (SASP) occur during senescence and depend on cGAS, a DNA sensor protein that can activate the innate immune response. cGAS has been shown to self-oligomerise to cause DNA compaction and it is preferentially enriched at centromeres during interphase. Its role at centromere, especially during senescence onset, is not known. Here, I found that cGAS is depleted from centromeres as cells proceed to senescent state, suggesting that its absence might influence centromere decompaction. I also found that in the interphase of cycling cells, cGAS is enriched at CENP-B bound centromeres.In summary, this work sheds light on the events occurring at centromere during early senescence. This will enhance our understanding of senescence progression that is relevant in the physio- and patho-logical context such as cancer
Language: English
Subfield: Physiology
Field: Medicine
Open Access status: green
OpenAlex ID: W7125088017
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