Eric J. Brown, Ph.D.
Associate Professor of Cancer Biology
Department: Cancer Biology
Graduate Group Affiliations
Contact information
Abramson Family Cancer Research Institute
Department of Cancer Biology
Perelman School of Medicine
University of Pennsylvania
514 BRB II/III
421 Curie Boulevard
Philadelphia, PA 19104-6160
Department of Cancer Biology
Perelman School of Medicine
University of Pennsylvania
514 BRB II/III
421 Curie Boulevard
Philadelphia, PA 19104-6160
Office: 215-746-2805
Fax: 215-573-2486
Fax: 215-573-2486
Email:
brownej@mail.med.upenn.edu
brownej@mail.med.upenn.edu
Publications
Links
Search PubMed for articles
Cell and Molecular Biology graduate group faculty webpage.
Abramson Institute Faculty Page
Search PubMed for articles
Cell and Molecular Biology graduate group faculty webpage.
Abramson Institute Faculty Page
Education:
B.A. (Genetics)
University of California at Berkeley, 1989.
Ph.D. (Immunology)
Harvard University, 1996.
Permanent linkB.A. (Genetics)
University of California at Berkeley, 1989.
Ph.D. (Immunology)
Harvard University, 1996.
Description of Research Expertise
Research InterestsThe importance of replication stress responses in preserving genome integrity and preventing cancer and aging.
Key words: ATR, Chk1, DNA damage checkpoints, DNA repair, replication fork stability, genome integrity, cancer, aging.
Description of Research
Maintenance of genome stability helps prevent cancer and other age-associated diseases. My laboratory studies the cellular processes that safeguard the genome and investigates how defects in these mechanisms impact tissue homoeostasis, age-associated diseases, cancer risk, and cancer treatments. We are particularly interested in processes that maintain genome stability during DNA replication. As a homostatic sensor of problems that commonly occur during DNA replication, the ATR protein kinase regulates a signal transduction cascade that activates the Chk1 protein kinase. These kinases prevent cell cycle progression and prevents the collapse of troubled DNA replication forks into DNA double strand breaks. The conditions that activate the ATR pathway during DNA replication include hyperproliferative signaling, oncogenic stress, replisome dysfunction, naturally occurring forms of DNA damage and inherently difficult-to-replicate DNA sequences. In aggregate, such problems are relatively common. Thus, ATR pathway, as a component of a multilayered network of DNA replication and repair factors, maintains genome stability, which influences both cancer initiation and progression, and the development of other age-associated pathologies. Using both mouse models and cell-based systems, we are investigating 1) how replication fork stability is maintained by ATR, 2) how hypomorphic suppression of the ATR-Chk1 pathway can serve as an effective cancer treatment, and how organismal genome stability is maintained through cell extrinsic mechanisms that preserve stem cell function.
Rotation Projects
Please contact Dr. Brown for information on potential rotation projects.
Lab personnel
Ryan Ragland, Postdoctoral Researcher
Yu-Chen Tsai, Postdoctoral Researcher
Michael Keller, Clinical Research Fellow
Nishita Shastri, Graduate Student
Sima Patel, Graduate Student
Sara Small, Graduate Student
Hani Mayassi, Research Specialist
Administrative Assistant
Laura M. Murillo
215-573-0908
murillo@exchange.upenn.edu
Selected Publications
David W. Schoppy, Ryan L. Ragland, Oren Gilad, Nishita Shastri, Ashley A. Peters, Matilde Murga, Oscar Fernandez-Capetillo, J. Alan Diehl, and Eric J. Brown: Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. Journal of Clinical Investigation 122(1): 241-252, 2012.Gilad, O., Nabet, B.L., Ragland, R.L., Schoppy, D.W., Smith, K.D., Durham, A.C., Brown, E.J.: Combining ATR suppression with oncogenic Ras synergystically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Research 70(23): 9693-9702, 2010.
Ruzankina, Y., Schoppy, D.W., Asare, A., Clark, C.E., Vonderheide, R.H., Brown, E.J.: Tissue regenerative delays and synthetic lethality in adult mice upon combined deletion of ATR and p53. Nature Genetics 41(10): 1144-1149, 2009.
Chanoux, R.A., Yin, B., Urtishak, K.A., Bassing, C.H., Brown, E.J.: ATR and H2AX cooperate in maintaining genome stability under replication stress. The Journal of Biological Chemistry 284(9): 5994-6003, 2009.
Smith, K.D., Fu, M.A., Brown, E.J.: Tim-Tipin dysfunction creates an indispensible reliance on the ATR-Chk1 pathway for continued DNA synthesis. The Journal of Cell Biology 187(1): 15-23, 2009.
Urtishak, K.A., Smith, K.D., Chanoux, R.A., Greenberg, R.A., Johnson, F.B., Brown, E.J.: Timeless maintains genomic stability and suppresses sister chromatid exchange during unperturbed DNA replication. The Journal of Biological Chemistry 284(13): 8777–8785, 2009.
Ruzankina, R., Asare, A., Brown, E.J.: Replicative stress, stem cells and aging. Mechanisms of Ageing and Development 129: 460-466, 2008.
Ruzankina, Y., Pinzon-Guzman, C., Asare, A., Ong, T., Pontano, L., Cotsarelis, G., Zediak, V.P., Velez, M., Bhandoola, A., Brown, E.J.: Deletion of the developmentally essential gene ATR in adult mice leads to premature aging phenotypes and stem cell loss. Cell Stem Cell 1: 113-126, 2007.
Gasser, S., Orsulic, S., Brown, E.J., Raulet, D.H.: The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436: 1186-1190, 2005.
Brown, E.J., Baltimore, D.: Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes & Development 17(5): 615-628, 2003.