Brendan D. Price, PhD
Office phone: 617-632-4946
Website: Price Lab
Preferred contact method: email
Area of ResearchHow the ATM Protein Regulates the DNA Damage Response
Dana-Farber Cancer Institute
450 Brookline Avenue
Jimmy Fund JF516
Boston, MA 02215
BiographyDr. Price received his PhD in 1985 from the University of Cambridge and his postdoctoral training at the Royal Marsden Hospital, London, and the University of Glasgow, Scotland. He has performed research into control of cellular signaling by the ras and p53 proteins. He joined DFCI in 1992 and currently performs basic laboratory research aimed at understanding how the ATM protein regulates the cellular response to radiation therapy.
ResearchHow the ATM Protein Regulates the DNA Damage Response
Most human cancers are treated by either chemotherapy or radiation, which target the DNA of tumor cells. However, the efficacy of these treatments varies greatly between different tumor types: many tumors are relatively resistant to radiation therapy, while others are more sensitive. Our long-term goal is to identify the key biochemical pathways that regulate sensitivity to radiation therapy and to identify novel therapeutic compounds that inhibit their function.
The inherited disease ataxia-telangiectasia (AT) is characterized by numerous defects, including increased sensitivity to radiation, defective DNA repair, loss of DNA damage-induced signaling pathways, and aberrant cell cycle control. The ATM protein, encoded by the AT gene, is a large protein kinase. ATM can phosphorylate many proteins involved in the two key responses to DNA damage - the activation of cell cycle checkpoints and the regulation of DNA repair. The ATM protein is therefore essential for coordinating the cells response to DNA damage.
A major effort in our laboratory is to identify how the ATM protein detects DNA damage and to determine how ATM relays this information to the DNA repair machinery. We have identified several essential motifs within the ATM protein structure, including a leucine zipper domain, which mediates protein-protein interactions, as well as an essential substrate binding domain located at the N-terminal of the ATM protein. Recently, we have identified a novel signaling pathway in which the activation of the ATM protein in response to DNA damage involves acetylation of ATM. This acetylation of ATM is brought about through the activation of the TIP60 histone acetyltransferase. TIP60 binds to the ATM protein; when ATM is recruited to sites of DNA damage, interactions between the damaged chromatin and the TIP60 protein lead to activation of TIP60's acetyltransferase activity, leading to acetylation and activation of the ATM protein.
A second major research area is to understand how chromatin structure impacts the repair of DNA damage. Chromatin is a dynamic structure containing both open, transcriptionally active regions (euchromatin) and compacted, transcriptionally inactive regions (heterochromatin). DNA damage within these distinct chromatin domains requires specific sets of proteins to alter chromatin structure and facilitate DNA reapir. We are currently examining the role of histone modifications, and in particular histone methylation, in regulating the ability of cells to detect and repair DNA damage. Our results indicate that a specific histone modification, H3K9me3, plays a critical role in DNA damage responses by regulating the recruitment and activation of protein complexes, including the NuA4 complex, to damaged chromatin. NuA4 then alters chromatin structure by faciltiating both the acetylation of histones and by decreasing nucleosome stability in the regions adjacent to to DNA breaks. This relaxation of the chromatin structure by NuA4 promotes DNA repair by facilitating the recruitment of DNA repair protiens such as brca1 and 53BP1 to sites of damage.
Our long term goal is to develop small molecule inhibitors of the enzymes which control histone methylation and demethylation as potential therapeutic agents. By modifying the levels of histone methylation in tumor cells, we expect to be able to manipulate the ability of cells to repair DNA damage, and therefore sensitize cells to chemotherapy or radiotherapy. Developing epigenetic therapy to directly modulate DNA repair pathways in tumor cells is therfore expected to lead to new therapies to treat cancer..
- Fernandes N, Sun Y, Chen S, Paul P, Shaw RJ, Cantley LC, Price BD. 2005. DNA-damage induced association of ATM with its target proteins requires a protein interaction domain in the N-terminus of ATM. J Biol Chem;280:15158-64.
- Sun Y, Jiang X, Fernandes N, Price BD. A role for the TIP60 histone acetyltransferase in the acetylation and activation of ATM.
Proc Natl Acad Sci U S A 2005;102:13182-7.
- Sun, Y., X. Jiang, and B. D. Price. 2010. Tip60: Connecting chromatin to DNA damage signaling. Cell Cycle, in press.
- Sun, Y., X. Jiang, Y. Xu, M. K. Ayrapetov, L. A. Moreau, J. R. Whetstine, and B. D. Price. 2009. Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat Cell Biol 11:1376-82.
- Sun, Y., Y. Xu, K. Roy, and B. D. Price. 2007. DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. Mol Cell Biol 27:8502-9.
- Jiang, X., Y. Sun, S. Chen, K. Roy, and B. D. Price. 2006. The FATC domains of PIKK proteins are functionally equivalent and participate in the Tip60-dependent activation of DNA-PKcs and ATM. J Biol Chem 281:15741-6.
- Sun, Yingli, PhD
- Xu, Ye, PhD
- Ayrapetov, Marina, PhD
- Xu, Chang, PhD
- Saydam, Nurten, PhD
- Johnson, Sarah, BS