Mechanisms of Aneuploidy-induced Telomere Replication Stress and Aneuploidy-induced Senescence

• Applicant: Professor Dr. Cagatay Günes
• Subject Area: Cell Biology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289797638

Ageing is the major risk factor for developing cancer. On the other hand, aneuploidy, a hallmark feature of carcinogenesis, and increases with age in humans but molecular mechanisms that induce aneuploidy or survival of aneuploid human cells remain to be defined. We have recently demonstrated that aneuploidy induces telomere replication stress and premature senescence, referred to as aneuploidy -induced senescence (AIS), in primary human fibroblasts (HFs) with intact checkpoints. Importantly, telomerase alleviates telomere replication stress and facilitates continuous proliferation of aneuploid HFs. A better understanding of the mechanisms is required to influence these processes in the context of ageing and carcinogenesis. We hypothesise that the proper progression of the replication fork, the coordinated expression of limiting factors and the activity of telomerase contribute to the survival of aneuploid cells. Here, due to their sequence composition and structure, telomeres have a vital function as they pose a challenge for the replication machinery. To improve our mechanistic understanding of the role of telomeres and telomerase activation and survival of AIS, three major goals are in the focus of this application:(i) The role of limiting factors in aneuploidy-induced telomere replication stress and AIS (ii) The role of helicases in alleviating telomere replication stress(iii) The role of telomerase in alleviating telomere replication stress and AIS

• DFG Programme: Research Grants