RT Journal Article
SR Electronic
T1 DNA damage and oxidizing conditions activate p53 through differential upstream signaling pathways
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.13.295220
DO 10.1101/2020.09.13.295220
A1 Tao Shi
A1 Paulien E. Polderman
A1 Boudewijn M.T. Burgering
A1 Tobias B. Dansen
YR 2020
UL http://biorxiv.org/content/early/2020/09/13/2020.09.13.295220.abstract
AB Stabilization and activation of the p53 tumour suppressor are triggered in response to various cellular stresses, including DNA damaging agents and elevated Reactive Oxygen Species (ROS) like H2O2. When cells are exposed to exogenously added H2O2, ATR/CHK1 and ATM/CHK2 dependent DNA damage signaling is switched on, suggesting that H2O2 induces both single and double strand breaks. These collective observations have resulted in the widely accepted model that oxidizing conditions lead to DNA damage that subsequently mediates a p53-dependent response like cell cycle arrest and apoptosis. However, H2O2 induces signaling through stress-activated kinases (SAPK, e.g., JNK and p38MAPK) that can activate p53. Here we dissect to what extent these pathways contribute to functional activation of p53 in response to oxidizing conditions. Collectively, our data suggest that p53 can be activated both by SAPK signaling and the DDR independently of each other, and which of these pathways is activated depends on the type of oxidant used. This implies that it could in principle be possible to modulate redox signaling to stimulate p53 without inducing collateral DNA damage, thereby limiting mutation accumulation in both healthy and tumor tissues.Competing Interest StatementThe authors have declared no competing interest.