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Brendan D. Price, PhD


Researcher


Researcher

  • Assistant Professor of Radiation Oncology, Harvard Medical School

Contact Information

  • Office Phone Number617-632-4946
  • Fax617-632-4599

Bio

Dr. 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.

Research

How 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..

Zhou J, Li J, Serafim RB, Ketchum S, Ferreira CG, Liu JC, Coe KA, Price BD, Yusufzai T. Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus. Nucleic Acids Res. 2018 May 04; 46(8):3891-3905.
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Gursoy-Yuzugullu O, Carman C, Price BD. Spatially restricted loading of BRD2 at DNA double-strand breaks protects H4 acetylation domains and promotes DNA repair. Sci Rep. 2017 Oct 10; 7(1):12921.
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Dhar S, Gursoy-Yuzugullu O, Parasuram R, Price BD. The tale of a tail: histone H4 acetylation and the repair of DNA breaks. Philos Trans R Soc Lond B Biol Sci. 2017 Oct 05; 372(1731).
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Ströbel T, Madlener S, Tuna S, Vose S, Lagerweij T, Wurdinger T, Vierlinger K, Wöhrer A, Price BD, Demple B, Saydam O, Saydam N. Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma. Sci Rep. 2017 Aug 29; 7(1):9674.
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Day TA, Layer JV, Cleary JP, Guha S, Stevenson KE, Tivey T, Kim S, Schinzel AC, Izzo F, Doench J, Root DE, Hahn WC, Price BD, Weinstock DM. Corrigendum: PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA. Nat Commun. 2017 Jun 13; 8:15918.
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Price BD. KDM5A demethylase: Erasing histone modifications to promote repair of DNA breaks. J Cell Biol. 2017 07 03; 216(7):1871-1873.
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Day TA, Layer JV, Cleary JP, Guha S, Stevenson KE, Tivey T, Kim S, Schinzel AC, Izzo F, Doench J, Root DE, Hahn WC, Price BD, Weinstock DM. PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA. Nat Commun. 2017 Apr 27; 8:15110.
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Gursoy-Yuzugullu O, Carman C, Serafim RB, Myronakis M, Valente V, Price BD. Epigenetic therapy with inhibitors of histone methylation suppresses DNA damage signaling and increases glioma cell radiosensitivity. Oncotarget. 2017 Apr 11; 8(15):24518-24532.
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Gursoy-Yuzugullu O, House N, Price BD. Patching Broken DNA: Nucleosome Dynamics and the Repair of DNA Breaks. J Mol Biol. 2016 05 08; 428(9 Pt B):1846-60.
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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 Jun 16; 112(24):7507-12.
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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 Oct 03; 452(4):1034-9.
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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 Jun 24; 111(25):9169-74.
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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 Jun 27; 50(6):908-18.
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Price BD, D'Andrea AD. Chromatin remodeling at DNA double-strand breaks. Cell. 2013 Mar 14; 152(6):1344-54.
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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 Dec; 178(6):604-8.
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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 Dec 14; 48(5):723-33.
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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 Nov 02; 586(21):3920-5.
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Xu Y, Xu C, Price BD. Mechanistic links between ATM and histone methylation codes during DNA repair. Prog Mol Biol Transl Sci. 2012; 110:263-88.
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Xu Y, Parmar K, Du F, Price BD, Sun Y. The radioprotective agent WR1065 protects cells from radiation damage by regulating the activity of the Tip60 acetyltransferase. Int J Biochem Mol Biol. 2011; 2(4):295-302.
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Ayrapetov MK, Xu C, Sun Y, Zhu K, Parmar K, D'Andrea AD, Price BD. Activation of Hif1a by the prolylhydroxylase inhibitor dimethyoxalyglycine decreases radiosensitivity. PLoS One. 2011; 6(10):e26064.
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Xu Y, Price BD. Chromatin dynamics and the repair of DNA double strand breaks. Cell Cycle. 2011 Jan 15; 10(2):261-7.
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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 Oct 04; 191(1):31-43.
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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(5):R71.
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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 Sep; 8(9):1217-26.
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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 Jul 02; 584(13):2926-30.
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Sun Y, Jiang X, Price BD. Tip60: connecting chromatin to DNA damage signaling. Cell Cycle. 2010 Mar 01; 9(5):930-6.
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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 Dec; 146(6):1208-14.
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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 Dec 01; 15(23):7238-45.
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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 Oct; 7(10):1655-62.
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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 Nov; 11(11):1376-82.
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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 Dec; 27(24):8502-9.
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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 Jun 01; 282(22):16577-84.
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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 Aug 07; 580(18):4353-6.
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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 Jun 09; 344(3):821-6.
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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 Jun 09; 281(23):15741-6.
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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 Sep 13; 102(37):13182-7.
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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 Apr 15; 280(15):15158-64.
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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 May 21; 32(9):e76.
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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 May 14; 317(4):1037-44.
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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 Sep 25; 22(41):6332-9.
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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 Sep; 17(5):365-74.
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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 Sep; 20(9):936-9.
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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 Aug; 20(2):139-47.
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Dana-Farber Cancer Institute
450 Brookline Avenue
Jimmy Fund JF516
Boston MA, 02215
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