Photo of Brendan D. Price,  PhD

Brendan D. Price, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-4946
Fax: (617) 632-4599


brendan_price@dfci.harvard.edu

Brendan D. Price, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Associate Professor, Radiation Oncology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

Work in the laboratory is focussed on examining the role of the ATM protein kinase in regulating DNA repair. ATM is the gene mutated in the hereditary disorder Ataxia Telangiectasia (AT). Patients with AT exhibit neurological dysfunction, increased incidence of cancer and extreme sensitivity to DNA damage. We have identified the Tip60 Histone acetyltransferase (HAT) as a key upstream regulator of ATM. Tip60 associates with the FATC domain of ATM. Activation of ATM by DNA damage is driven by the Tip60-dependent acetylation of the ATM protein. This acetylation of ATM activates the kinase activity of the ATM protein, resulting in phosphorylation of key down stream target proteins and the co-ordinate repair of DNA. Current experiments are focussed on understanding how histone modifications at sites of DNA damage mediate activation of the ATM-Tip60 complex. In addition, we are identifying inhibitors of Tip60 as potential chemo- and radio-sensitizers, and identifiying Tip60 mutations in human tumors.

Publications

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  • Gursoy-Yuzugullu O, Ayrapetov MK, Price BD. Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair. Proc Natl Acad Sci U S A 2015; 112:7507-12. PubMed
  • Du F, Zhang M, Li X, Yang C, Meng H, Wang D, Chang S, Xu Y, Price B, Sun Y. Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair. Biochem Biophys Res Commun 2014; 452:1034-9. PubMed
  • Ayrapetov MK, Gursoy-Yuzugullu O, Xu C, Xu Y, Price BD. DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin. Proc Natl Acad Sci U S A 2014. PubMed
  • Madlener S, Ströbel T, Vose S, Saydam O, Price BD, Demple B, Saydam N. Essential role for mammalian apurinic/apyrimidinic (AP) endonuclease Ape1/Ref-1 in telomere maintenance. Proc Natl Acad Sci U S A 2013; 110:17844-9. PubMed
  • Park E, Kim H, Kim JM, Primack B, Vidal-Cardenas S, Xu Y, Price BD, Mills AA, D'Andrea AD. FANCD2 activates transcription of TAp63 and suppresses tumorigenesis. Mol Cell 2013; 50:908-18. PubMed
  • Price BD, D'Andrea AD. Chromatin remodeling at DNA double-strand breaks. Cell 2013; 152:1344-54. PubMed
  • Xu Y, Ayrapetov MK, Xu C, Gursoy-Yuzugullu O, Hu Y, Price BD. Histone H2A.Z controls a critical chromatin remodeling step required for DNA double-strand break repair. Mol Cell 2012. PubMed
  • Berbeco RI, Korideck H, Ngwa W, Kumar R, Patel J, Sridhar S, Johnson S, Price BD, Kimmelman A, Makrigiorgos GM. DNA damage enhancement from gold nanoparticles for clinical MV photon beams. Radiat Res 2012. PubMed
  • Xu C, Xu Y, Gursoy-Yuzugullu O, Price BD. The histone variant macroH2A1.1 is recruited to DSBs through a mechanism involving PARP1. FEBS Lett 2012; 586:3920-5. PubMed
  • Xu Y, Price BD. Chromatin dynamics and the repair of DNA double strand breaks. Cell Cycle 2011; 10:261-7. PubMed
  • Xu Y, Sun Y, Jiang X, Ayrapetov MK, Moskwa P, Yang S, Weinstock DM, Price BD. The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair. J Cell Biol 2010; 191:31-43. PubMed
  • Weng D, Cunin MC, Song B, Price BD, Eller MS, Gilchrest BA, Calderwood SK, Gong J. Radiosensitization of mammary carcinoma cells by telomere homolog oligonucleotide pretreatment. Breast Cancer Res 2010; 12:R71. PubMed
  • Lin CI, Whang EE, Donner DB, Du J, Lorch J, He F, Jiang X, Price BD, Moore FD, Ruan DT. Autophagy induction with RAD001 enhances chemosensitivity and radiosensitivity through Met inhibition in papillary thyroid cancer. Mol Cancer Res 2010; 8:1217-26. PubMed
  • Jiang X, Xu Y, Price BD. Acetylation of H2AX on lysine 36 plays a key role in the DNA double-strand break repair pathway. FEBS Lett 2010; 584:2926-30. PubMed
  • Sun Y, Jiang X, Price BD. Tip60: Connecting chromatin to DNA damage signaling. Cell Cycle 2010. PubMed
  • Lin CI, Whang EE, Abramson MA, Jiang X, Price BD, Donner DB, Moore FD, Ruan DT. Autophagy: a new target for advanced papillary thyroid cancer therapy. Surgery 2009; 146:1208-14. PubMed
  • Kim K, Pollard JM, Norris AJ, McDonald JT, Sun Y, Micewicz E, Pettijohn K, Damoiseaux R, Iwamoto KS, Sayre JW, Price BD, Gatti RA, McBride WH. High-throughput screening identifies two classes of antibiotics as radioprotectors: tetracyclines and fluoroquinolones. Clin Cancer Res 2009; 15:7238-45. PubMed
  • Sun Y, Jiang X, Xu Y, Ayrapetov MK, Moreau LA, Whetstine JR, Price BD. Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat Cell Biol 2009; 11:1376-82. PubMed
  • Lin CI, Whang EE, Donner DB, Jiang X, Price BD, Carothers AM, Delaine T, Leffler H, Nilsson UJ, Nose V, Moore FD, Ruan DT. Galectin-3 targeted therapy with a small molecule inhibitor activates apoptosis and enhances both chemosensitivity and radiosensitivity in papillary thyroid cancer. Mol Cancer Res 2009; 7:1655-62. PubMed
  • Sun Y, Xu Y, Roy K, Price BD. DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. Mol Cell Biol 2007; 27:8502-9. PubMed
  • Fernandes ND, Sun Y, Price BD. Activation of the kinase activity of ATM by retinoic acid is required for CREB-dependent differentiation of neuroblastoma cells. J Biol Chem 2007; 282:16577-84. PubMed
  • Sun Y, Jiang X, Chen S, Price BD. Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation. FEBS Lett 2006; 580:4353-6. PubMed
  • Jiang X, Sun Y, Chen S, Roy K, Price BD. The FATC domains of PIKK proteins are functionally equivalent and participate in the Tip60-dependent activation of DNA-PKcs and ATM. J Biol Chem 2006; 281:15741-6. PubMed
  • Roy K, Wang L, Makrigiorgos GM, Price BD. Methylation of the ATM promoter in glioma cells alters ionizing radiation sensitivity. Biochem Biophys Res Commun 2006; 344:821-6. PubMed
  • Sun Y, Jiang X, Chen S, 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. PubMed
  • Fernandes N, Sun Y, Chen S, Paul P, Shaw RJ, Cantley LC, Price BD. DNA damage-induced association of ATM with its target proteins requires a protein interaction domain in the N terminus of ATM. J Biol Chem 2005; 280:15158-64. PubMed
  • Chen S, Wang G, Makrigiorgos GM, Price BD. Stable siRNA-mediated silencing of ATM alters the transcriptional profile of HeLa cells. Biochem Biophys Res Commun 2004; 317:1037-44. PubMed
  • Wang G, Brennan C, Rook M, Wolfe JL, Leo C, Chin L, Pan H, Liu WH, Price B, Makrigiorgos GM. Balanced-PCR amplification allows unbiased identification of genomic copy changes in minute cell and tissue samples. Nucleic Acids Res 2004; 32:e76. PubMed
  • Chen S, Paul P, Price BD. ATM's leucine-rich domain and adjacent sequences are essential for ATM to regulate the DNA damage response. Oncogene 2003; 22:6332-9. PubMed
  • Makrigiorgos GM, Chakrabarti S, Zhang Y, Kaur M, Price BD. A PCR-based amplification method retaining the quantitative difference between two complex genomes. Nat Biotechnol 2002; 20:936-9. PubMed
  • Kaur M, Zhang Y, Liu WH, Tetradis S, Price BD, Makrigiorgos GM. Ligation of a primer at a mutation: a method to detect low level mutations in DNA. Mutagenesis 2002; 17:365-74. PubMed
  • Zhang Y, Kaur M, Price BD, Tetradis S, Makrigiorgos GM. An amplification and ligation-based method to scan for unknown mutations in DNA. Hum Mutat 2002; 20:139-47. PubMed
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