Transient senescence in tissue repair - Genetic and metabolic regulation of resistance to apoptosis during injury-induced G2-stalling in Drosophila

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The exposed position of epithelia makes them susceptible to injury and damage. The restoration of homeostasis after damage relies on the proper spatio-temporal control of distinct cell behaviors, such as damage-induced apoptosis, compensatory proliferation and tissue remodeling. While it is established that in Drosophila imaginal discs these processes are largely coordinated by the stress response pathway JNK, we still fail to understand how spatial patterns of these behaviors are controlled and how feed-back and crosstalk between them guides tissue repair process. We recently demonstrate that JNK signaling induces a dose-dependent extension of the G2-phase of the cell cycle in tissue damage and tumors resulting in either transient stalling or a prolonged but reversible cell cycle arrest. We found that stalling in G2 induces senescence hallmarks, thereby offering the opportunity to dissect the physiological requirements of transient senescence programs for tissue repair in vivo. We will utilize classical cell biological and genetic approaches to specifically examine how G2 stalling induces cell-cycle-dependent resistance to apoptosis. Moreover, we will begin to characterize the metabolic programs of wound healing and tissue repair. By combining our core expertise in stress signaling cascades and their proliferative and apoptotic effector programs with the emerging field of metabolism, we aim to uncover fundamental principles and senolytic strategies to address medical conditions with tremendous societal impact, such as chronic wound healing pathologies and inflammation-associated disorders of ageing, diabetes and cancer.