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Eric J. Brown, Ph.D.

Eric J. Brown, Ph.D.

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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
Office: 215-746-2805
Fax: 215-573-2486
Education:
B.A. (Genetics)
University of California at Berkeley, 1989.
Ph.D. (Immunology)
Harvard University, 1996.
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Description of Research Expertise

Research Interests
The importance of replication stress responses in maintaining genome integrity and preventing aging and cancer.

Key words: ATR, Chk1, DNA damage checkpoints, DNA repair, replication fork stability, genome integrity, stem cell maintenance, tissue regeneration, aging and cancer.

Description of Research

Maintaining the integrity of the genome delays the onset of cancer and other age-associated diseases. The processes that safeguard the genome are particularly important during DNA replication, when the normally stable DNA duplex structure is rendered susceptible to recombination events and collapse. My laboratory studies how genome integrity is maintained during DNA replication and investigates how defects in these mechanisms impact tissue homoeostasis, age-associated diseases, and cancer risk and treatment.

As a sensor of problems that commonly occur during DNA replication, the ATR protein kinase regulates a signal transduction cascade that inhibits cell cycle progression and prevents the collapse of troubled DNA replication forks. The conditions that activate the ATR pathway during DNA replication include excessive growth-factor signaling, oncogenic stress, replisome dysfunction, inherently difficult-to-replicate DNA sequences and naturally occurring forms of DNA damage. In aggregate, such problems are relatively common. Thus, ATR pathway maintains genome stability in during cell proliferation, which occurs constitutively during tissue homeostasis and cancer growth. Importantly, at the organismal level, the integrity of the genome is also assured through maintaining the regenerative potential and quality of adult stem cells. Using mouse models and cell-based systems, we are investigating 1) how replication fork stability is regulated by ATR, 2) how hypomorphic suppression of the ATR-Chk1 pathway can serve as an effective cancer treatment, and 3) how organismal genome stability is sustained through cell intrinsic and 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
Nishita Shastri, Graduate Student
Sima Patel, Graduate Student
Sara Small, Graduate Student
Theonie Anastassiadis, Graduate Student
Rebecca Rivard, Graduate student
Euri Parios, Undergraduate researcher
Jessica Tang, Undergraduate researcher
Justin Puckett, Undergraduate researcher

Administrative Assistant
Laura M. Murillo
215-573-0908
murillo@exchange.upenn.edu

Selected Publications

Schoppy DW, Ragland RL, Gilad O, Shastri N, Peters AA, Murga M, Fernandez-Capetillo O, Diehl JA, Brown EJ: 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.

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Last updated: 05/06/2014
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