Int J Biochem Mol Biol 2011;2(4):295-302
Original Article
The radioprotective agent WR1065 protects cells from radiation damage by regulating
the activity of the Tip60 acetyltransferase
Ye Xu, Kalindi Parmar,Fengxia Du, Brendan D. Price, Yingli Sun
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA; 2Disease
Genomics and Individualized Medicine Key Lab, Beijing Institute of Genomics, Chinese Academy of Sciences, No 7 Beitucheng West Road,
Chaoyang District, Beijing 100029, PR China.
Received August 24, 2011; accepted September 28, 2011; Epub October 20, 2011; Published December 15, 2011
Abstract: 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. (IJBMB1108003)
Keywords:
Full Text PDF
Address all correspondence to:
Dr. Brendan D. Price
Department of Radiation Oncology
Dana-Farber Cancer Institute, Harvard Medical School,
44 Binney St, Boston
MA 02115, USA.
E-mail: brendan_price@dfci.harvard.edu
Original Article
The radioprotective agent WR1065 protects cells from radiation damage by regulating
the activity of the Tip60 acetyltransferase
Ye Xu, Kalindi Parmar,Fengxia Du, Brendan D. Price, Yingli Sun
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA; 2Disease
Genomics and Individualized Medicine Key Lab, Beijing Institute of Genomics, Chinese Academy of Sciences, No 7 Beitucheng West Road,
Chaoyang District, Beijing 100029, PR China.
Received August 24, 2011; accepted September 28, 2011; Epub October 20, 2011; Published December 15, 2011
Abstract: 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. (IJBMB1108003)
Keywords:
Full Text PDF
Address all correspondence to:
Dr. Brendan D. Price
Department of Radiation Oncology
Dana-Farber Cancer Institute, Harvard Medical School,
44 Binney St, Boston
MA 02115, USA.
E-mail: brendan_price@dfci.harvard.edu
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