title: The Δ133p53 Isoform Reduces Wtp53-induced Stimulation of DNA Pol γ Activity in the Presence and Absence of D4T.
abstract: The mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTIs) is due to the inhibition of mitochondrial DNA (mtDNA) polymerase γ (pol γ). Previous studies have shown that wild type p53 (wtp53) can interact with pol γ and mtDNA to enhance mitochondrial DNA base excision repair (mtBER) activity and increase the accuracy of DNA synthesis. The N-terminal transactivation domain and central specific DNA-binding domain of p53 play critical roles in the stimulation of BER. In this study, we identified the possible roles of wtp53, Δ40p53 and Δ133p53 in regulating mtDNA pol γ activity in cells with d4T treatment. The results show that Δ40p53 and Δ133p53 can exist in mitochondrial fragments and form polymers with themselves or wtp53. Unlike wtP53, Δ133p53 alone cannot increase DNA pol γ activity. More importantly, we found that Δ133p53 played a negative role in p53 stimulation of DNA pol γ activity when studied in d4T-treated and d4T-untreated mitochondrial extracts. Gel shift data also indicate that Δ40p53 and Δ133p53 cannot interact with APE. Wtp53 and Δ40p53 can act antagonize the effect of d4T inhibition of DNA pol γ activity. However, when wtp53 interacted with Δ133p53, DNA pol γ activity was significantly decreased.
  
  
  CONCLUSIONS
  Δ133p53 negatively regulates p53's stimulation of pol γ in the presence and absence of d4T.
authors.affiliation: 1Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: 2The Affiliated Hospital of Qingdao University, Organ Transplantation Center, Qingdao, Shandong 266003, China.
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Zang
authors.affiliation: 1Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Guo
authors.affiliation: 1Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Feili
authors.initials: F
authors.lastname: Wei
authors.affiliation: 1Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Jiming
authors.initials: J
authors.lastname: Yin
authors.affiliation: 1Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Pang
authors.affiliation: 1Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
keywords: mitochondria; mtBER; mtDNA; p53 isoform; stavudine (d4T)