Involvement of p38MAPK-ATF2 signaling pathway in alternariol induced DNA polymerase β expression

Base excision repair (BER) systems are important for maintaining the integrity of genomes in mammalian cells. Aberrant DNA bases or broken single strands can be repaired by BER. Consequently, DNA lesions, which may be caused by cancer and aging, have a close association with BER procedure. DNA polymerase beta (pol beta) is a critical BER enzyme that can excise 5'-sugar phosphate prior to adding a nucleotide in the gap by its function as a DNA polymerase in the BER process. However, DNA pol beta is an error-prone DNA polymerase, and overexpressing pol beta increases the cellular spontaneous mutation rate. DNA pol beta overexpression has been identified in various human tumors, which implies that DNA pol beta overexpression has a close association with tumorigenesis. The present study showed that alternariol (AOH), a secondary product of a fungus that is found in grains and fruits, could cause DNA damage to NIH3T3 cells in a single cell gel electrophoresis, and that 2, 10 and 20 mu M AOH induced DNA pol beta overexpression in a dose-dependent manner. In the process, the level of phosphorylation of mitogen-activated protein kinase 14 (p38) mitogen-activated protein kinase (MAPK) and activating transcription factor 2 (ATF2) was increased. In addition, SB203580, a p38MAPK inhibitor, resulted in decreased DNA pol beta expression. Small hairpin RNA-p38MAPK had the same effect; notably, DNA pol beta expression was downregulated in p38MAPK knockdown cells. These data suggest that the p38MAPK-ATF2 signaling pathway may be involved in DNA pol beta expression induced by AOH.