TSC loss distorts DNA replication programme and sensitises cells to genotoxic stress
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TSC loss distorts DNA replication programme and sensitises cells to genotoxic stress. / Pai, Govind M; Zielinski, Alexandra; Koalick, Dennis; Ludwig, Kristin; Wang, Zhao-Qi; Borgmann, Kerstin; Pospiech, Helmut; Rubio, Ignacio.
In: ONCOTARGET, Vol. 7, No. 51, 20.12.2016, p. 85365-85380.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - TSC loss distorts DNA replication programme and sensitises cells to genotoxic stress
AU - Pai, Govind M
AU - Zielinski, Alexandra
AU - Koalick, Dennis
AU - Ludwig, Kristin
AU - Wang, Zhao-Qi
AU - Borgmann, Kerstin
AU - Pospiech, Helmut
AU - Rubio, Ignacio
PY - 2016/12/20
Y1 - 2016/12/20
N2 - Tuberous Sclerosis (TSC) is characterized by exorbitant mTORC1 signalling and manifests as non-malignant, apoptosis-prone neoplasia. Previous reports have shown that TSC-/- cells are highly susceptible to mild, innocuous doses of genotoxic stress, which drive TSC-/- cells into apoptotic death. It has been argued that this hypersensitivity to stress derives from a metabolic/energetic shortfall in TSC-/- cells, but how metabolic dysregulation affects the DNA damage response and cell cycle alterations in TSC-/- cells exposed to genotoxic stress is not understood. We report here the occurrence of futile checkpoint responses and an unusual type of replicative stress (RS) in TSC1-/- fibroblasts exposed to low-dose genotoxins. This RS is characterized by elevated nucleotide incorporation rates despite only modest origin over-firing. Strikingly, an increased propensity for asymmetric fork progression and profuse chromosomal aberrations upon mild DNA damage confirmed that TSC loss indeed proved detrimental to stress adaptation. We conclude that low stress tolerance of TSC-/- cells manifests at the level of DNA replication control, imposing strong negative selection on genomic instability that could in turn detain TSC-mutant tumours benign.
AB - Tuberous Sclerosis (TSC) is characterized by exorbitant mTORC1 signalling and manifests as non-malignant, apoptosis-prone neoplasia. Previous reports have shown that TSC-/- cells are highly susceptible to mild, innocuous doses of genotoxic stress, which drive TSC-/- cells into apoptotic death. It has been argued that this hypersensitivity to stress derives from a metabolic/energetic shortfall in TSC-/- cells, but how metabolic dysregulation affects the DNA damage response and cell cycle alterations in TSC-/- cells exposed to genotoxic stress is not understood. We report here the occurrence of futile checkpoint responses and an unusual type of replicative stress (RS) in TSC1-/- fibroblasts exposed to low-dose genotoxins. This RS is characterized by elevated nucleotide incorporation rates despite only modest origin over-firing. Strikingly, an increased propensity for asymmetric fork progression and profuse chromosomal aberrations upon mild DNA damage confirmed that TSC loss indeed proved detrimental to stress adaptation. We conclude that low stress tolerance of TSC-/- cells manifests at the level of DNA replication control, imposing strong negative selection on genomic instability that could in turn detain TSC-mutant tumours benign.
U2 - 10.18632/oncotarget.13378
DO - 10.18632/oncotarget.13378
M3 - SCORING: Journal article
C2 - 27863419
VL - 7
SP - 85365
EP - 85380
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 51
ER -
