Cancer arises from a series of rare mutageneic steps often resulting in genome instability (GI) (1). Yet the initial trigger for GI remains unclear. In several eukaryote model organisms and in humans, telomere erosion over time is suggested to be an intrinsic source of GI (2-4). In this project, we wish to characterize the mechanisms involved in the establishment of GI triggered by telomere erosion and to decipher their link to the escape from replicative senescence (RS), a prerequisite of cancer transformation. Using budding yeast Saccharomyces cerevisiae as a model, which has been used for major discoveries in the field of telomere biology and GI, our results will help defining cancer prevention strategies and better understand the increased emergence of tumors with age.



Telomeres cap the ends of chromosomes to maintain genome integrity by preventing the ends being recognized and processed as accidental chromosomal breaks (5-7). Telomere length is maintained by telomerase reverse transcriptase. However, telomerase activity is down-regulated in many human somatic cells and telomeres progressively shorten due to the DNA end replication problem. When telomeres fall below a critical length, they activate the DNA damage checkpoints in a permanent and irreversible manner and cells enter RS (8, 9). Cancer cells are rare cells that have bypassed this proliferation barrier through mutations in the DNA damage checkpoint pathway. It is believed that this occasional loss of checkpoint proficiency increases the risk of recruiting DNA damage repair activities that then degrade, fuse, or recombine dysfunctional telomeres (10). Subsequently, a subset of cells may be selected that abnormally reactivate telomerase expression or activate alternative lengthening of telomere (ALT), which includes ill-defined mechanisms based on homology-directed repair (HDR) at telomeres. These cells display and may continuously accumulate a high degree of genomic instability, a major cancer feature (10, 11). Therefore, while telomere shortening generally suppress oncogenesis, it can occasionally promote it. Yet, the pathways involved in the emergence of ALT and GI when telomeres are eroded remain to be established. Furthermore, oxidative–stress–induced damage and mitochondrial defects have been proposed as a source of cell-to-cell variations in senescence and telomere degradations that could exacerbate the effects of GI as telomeres erode (12-16). However, current direct links between telomeres and mitochondrial metabolism remain controversial.



Our recent multidisciplinary research using S. cerevisiae as a model has demonstrated that all three phenomena - (i) replicative senescence, (ii) ALT, and (iii) GI - are driven by a single cellular entity: the shortest telomere (17, 18). This insight paves the way for understanding the earliest events that initiate oncogenesis and highlights the potential of telomere length as a predictive marker for cancer susceptibility.



The present project comprises two independent axis. One one hand we will investigate the role of double-strand break repair pathways in telomere processing and ALT/GI. On another hand, we will examine the role of mitochondrial dysfunction and reactive oxygen species (ROS) level modification in contributing to genomic instability during replicative senescence.
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Cancer arises from a series of rare mutageneic steps often resulting in genome instability (GI) (1). Yet the initial trigger for GI remains unclear. In several eukaryote model organisms and in humans, telomere erosion over time is suggested to be an intrinsic source of GI (2-4). In this project, we wish to characterize the mechanisms involved in the establishment of GI triggered by telomere erosion and to decipher their link to the escape from replicative senescence (RS), a prerequisite of cancer transformation. Using budding yeast Saccharomyces cerevisiae as a model, which has been used for major discoveries in the field of telomere biology and GI, our results will help defining cancer prevention strategies and better understand the increased emergence of tumors with age.



Telomeres cap the ends of chromosomes to maintain genome integrity by preventing the ends being recognized and processed as accidental chromosomal breaks (5-7). Telomere length is maintained by telomerase reverse transcriptase. However, telomerase activity is down-regulated in many human somatic cells and telomeres progressively shorten due to the DNA end replication problem. When telomeres fall below a critical length, they activate the DNA damage checkpoints in a permanent and irreversible manner and cells enter RS (8, 9). Cancer cells are rare cells that have bypassed this proliferation barrier through mutations in the DNA damage checkpoint pathway. It is believed that this occasional loss of checkpoint proficiency increases the risk of recruiting DNA damage repair activities that then degrade, fuse, or recombine dysfunctional telomeres (10). Subsequently, a subset of cells may be selected that abnormally reactivate telomerase expression or activate alternative lengthening of telomere (ALT), which includes ill-defined mechanisms based on homology-directed repair (HDR) at telomeres. These cells display and may continuously accumulate a high degree of genomic instability, a major cancer feature (10, 11). Therefore, while telomere shortening generally suppress oncogenesis, it can occasionally promote it. Yet, the pathways involved in the emergence of ALT and GI when telomeres are eroded remain to be established. Furthermore, oxidative–stress–induced damage and mitochondrial defects have been proposed as a source of cell-to-cell variations in senescence and telomere degradations that could exacerbate the effects of GI as telomeres erode (12-16). However, current direct links between telomeres and mitochondrial metabolism remain controversial.



Our recent multidisciplinary research using S. cerevisiae as a model has demonstrated that all three phenomena - (i) replicative senescence, (ii) ALT, and (iii) GI - are driven by a single cellular entity: the shortest telomere (17, 18). This insight paves the way for understanding the earliest events that initiate oncogenesis and highlights the potential of telomere length as a predictive marker for cancer susceptibility.



The present project comprises two independent axis. One one hand we will investigate the role of double-strand break repair pathways in telomere processing and ALT/GI. On another hand, we will examine the role of mitochondrial dysfunction and reactive oxygen species (ROS) level modification in contributing to genomic instability during replicative senescence.
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Début de la thèse : 01/10/2025
WEB : http://lbmce.ibpc.fr/telomere-biology/

Funding category: Contrat doctoral

Concours pour un contrat doctoral