Arsenic-induced S phase cell cycle lengthening is associated with ROS generation, p53 signaling and CDC25A expression

- NaAsO2-induced S phase arrest relies on a p53-wild type background.
- Transcriptional activity of p53 is necessary for NaAsO2 induced S phase arrest.
- p53 protects cells to ROS accumulation by regulating stress responsive genes.
- CDC25A is down-regulated by an indirect p53-dependent mechanism involving ATF3.

Cellular response to arsenic is strongly dependent on p53 functional status. Primarily arresting the cell cycle in G1 or G2/M phases, arsenic treatment also induces an increase in the S-phase time in wild-type p53 cells. In contrast, cells with a non-functional p53 display only a subtle increase in the S phase, indicating arsenic differentially affects the cell cycle depending on p53 status. Importantly, it has been reported that arsenic induces reactive oxygen species (ROS), a process counteracted by p53. To evaluate the participation of p53 in the lengthening of the S phase and the connection between the transient cell cycle arrest and oxidative stress, we evaluated the cell response to arsenic in MCF-7 and H1299 cells, and analyzed p53's role as a transcription factor in regulating genes involved in ROS reduction and S phase transition. Herein, we discovered that arsenic induced an increase in the population of S phase cells that was dependent on the presence and transcriptional activity of p53. Furthermore, for the first time, we demonstrate that arsenic activates p53-dependent transcription of ROS detoxification genes, such as SESN1, and by an indirect mechanism involving ATF3, genes that could be responsible for the S phase cell cycle arrest, such as CDC25A.