DNA Damage Response Regulates Initiation of in Liver Regeneration Following Acetaminophen Overdose.

Acetaminophen (APAP) overdose is the leading cause of Acute Liver Failure (ALF) with limited treatment options. It is known that liver regeneration following APAP induced ALF is a deciding factor in the final outcome. Previous studies from our laboratory using incremental dose model involving a regenerating (300 mg/kg, APAP300) and a non-regenerating (600 mg/kg, APAP600) dose of APAP in mice have revealed several pro- regenerative pathways that regulate regeneration after APAP overdose. Here we report that DNA damage and repair mechanisms regulate initiation liver regeneration following APAP overdose. Mice treated with non-regenerating APAP600 dose showed prolonged expression of pH2AX, a marker of the DNA double strand break (DSB) than APAP300. In regenerating APAP300 dose treated mice H2AX was rapidly dephosphorylated at Tyr142 indicating timely DNA repair. Expression of several DNA repair proteins was substantially lower in APAP600. Poly (ADP) ribose polymerase (PARP) activation, involved in DNA repair, was significantly higher in APAP300 group compared to APAP600 group. Activation of p53, the major cell cycle checkpoint protein, was significantly higher in APAP600 as demonstrated by substantially higher expression of its target genes. Taken together, these data show that massive DNA double damage occurs in high dose APAP toxicity and lack of prompt DSB repair after APAP overdose leads to prolonged growth arrest, proliferative senescence resulting in inhibited liver regeneration.