The role of mTOR signalling pathway as a susceptibility factor in genotoxic stress-induced cell death

Tuberous Sclerosis manifests as non-malignant apoptotic neoplasia. Exorbitant mTORC1 signalling can sensitise TSC-/- cells to stress-induced death. Seminal reports identified that TSC-/- cells are susceptible to mild genotoxic stress, in part by augmented p53 function. Studies thereafter unveiling energetic shortfall due to unmet anabolic demand, refined our understanding of the stress-sensitive phenotype. However, the nature of cell cycle alterations in TSC-/- cells ultimately causing hypersensitivity to genotoxic stress is poorly understood. We report futile checkpoint responses and unusual replicative stress in TSC1-/- fibroblasts exposed to low-dose genotoxins characterized by elevated nucleotide incorporation rates despite only modest origin over-firing. Strikingly, an increased propensity for asymmetric fork progression and profuse chromosomal aberrations under external genotoxic stress suggests that constitutive mTORC1 activity proves detrimental to stress adaptation. We conclude that fundamentally slower DNA synthesis at individual forks and low stress tolerance imposes negative selection on genomic instability and could detain TSC-mutant tumours benign.