The radioprotective agent WR1065 protects cells from radiation damage by regulating the activity of the Tip60 acetyltransferase

International Journal of Biochemistry and Molecular Biology

Ye Xu¹  Kalindi Parmar¹  Brendan D Price¹  Fengxia Du¹  Yingli Sun¹ 

关键词: Aminothiol WR1065;    ionizing radiation;    prevention;    radiation injury;    Tip60 acetyltransferase;   

DOI  :  

学科分类：生物化学/生物物理

来源: e-Century Publishing Corporation

【 摘 要 】

Background: The aminothiol WR1065 is a highly effective free radical scavenger which can protect cells from the cytotoxic effects of ionizing radiation. Currently, WR1065 is used clinically to protect patients from radiation injury occurring during radiation therapy protocols. However, it is becoming increasingly clear that WR1065 can alter radiosensitivity through a mechanism which is independent of its ability to function as a free radical scavenger. Here, we examined the ability of WR1065 to directly regulate signaling pathways involved in the DNA damage response. Methodology: The ability of WR1065 to enhance the survival of irradiated bone marrow cells and primary cultures was established. DNA damage signaling was monitored by measuring activation of the ATM kinase by western blot analysis and activation of Tip60 using an in vitro acetylation assay. Tip60 function was abrogated by expression of a catalytically inactive Tip60, and the effect on radiosensitivity evaluated. Principal findings: Treatment of cells with WR1065 led to a small but significant increase in the kinase activity of ATM. Further, WR1065 robustly activated the Tip60 acetyltransferase, which is a key upstream regulator of the ATM kinase. In addition, WR1065 directly activated the acetyltransferase activity of purified Tip60 in vitro, indicating a direct interaction between WR1065 and Tip60. Finally, cells with reduced levels of Tip60 activity exhibited a significant reduction in radioprotection by WR1065. Conclusions: Direct regulation of Tip60's acetyltransferase activity by WR1065 makes a significant contribution to the radioprotective effects of WR1065. Activators of Tip60 may therefore make effective clinical radioprotectors.

【 授权许可】

Unknown