Eric J. Brown, Ph.D.
Assistant Professor, Dept of Cancer Biology

Cancer Biology Program

Address

514 Biomedical Rsch Bldg II/III (Office)
525 Biomedical Rsch Bldg II/III (Lab)
421 Curie Boulevard
Philadelphia, PA 19104-6140

Office tel.: 215 746-2805
Lab tel.: 215 746-5505
Fax: 215 573-2486
E-mail: brownej@mail.med.upenn.edu


EDUCATION
University of California at Berkeley: BA (Genetics), 1989.

Harvard University: PhD (Immunology), 1996.

Research Intersests

• Role of DNA damage responses in preserving genome integrity and preventing cancer.

Key words: DNA damage, checkpoints, cell cycle, genome integrity, DNA repair, ATR, ATM, cancer, aging.

Search PubMed for articles

Description of Research

Maintaining the integrity of the genome prevents cancer-causing events, like loss of heterozygosity and chromosome translocations. We have shown that the ATR (ATM and Rad3-related) protein kinase is essential for genome stability and suppresses cancer in mice. As a central and upstream regulator of a signal transduction cascade activated by stalled DNA replication, ATR may stabilize the genome by preventing stalled DNA replication forks from collapsing into double strand breaks. Since DNA replication stalling occurs in every cell cycle, failure of the ATR-mediated pathway to correctly respond to stalled DNA replication forks may be a major source of the genetic deletions and translocations that cause cancer and other age-related disorders.

ATR itself has no known DNA processing activity; therefore, ATR’s ability to prevent double strand break generation in the face of stalled DNA replication is likely mediated through downstream effectors. My laboratory has set out to determine what genes are regulated by ATR, how these genes stabilize stalled DNA replication forks and how these genes cooperate to prevent cancer and premature aging.

Recent Publications

Y. Ruzankina, C. Pinzon-Guzman, A. Asare, T. Ong, L. Pontano, G. Cotsarelis, V. P. Zediak, M. Velez, A. Bhandoola, and E. J. Brown (2007). 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.

S. Gasser, S. Orsulic, E. J. Brown, and D. H. Raulet (2005). The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186-90.

E. J. Brown (2003). The ATR-independent DNA replication checkpoint. Cell Cycle 2, 188-189.

E. J. Brown and D. Baltimore (2003). Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes & Dev. 17, 615-628.

E. J. Brown (2003). Analysis of cell cycle checkpoints and genomic integrity in early lethal knockouts. Methods Mol Biol. 280, 201-12.

C. Lois, E. J. Hong, S. Pease, E. J. Brown and D. Baltimore (2002). Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science. 295, 868-72.

E. J. Brown and D. Baltimore (2000). ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes & Dev. 14, 397-402.

Lab

Rotation Projects

1. Genome maintenance: We have demonstrated that ATR is required to maintain genome integrity, even in the absence of exogenous DNA damage. However, ATR itself has no DNA processing activity. Therefore, we are testing the hypothesis that the ATR protein kinase maintains genome integrity by regulating DNA repair genes through phosphorylation. This possibility is being investigated through both genetic and biochemical means.
   
   
2. Control of mitotic entry: We have shown that entry into M phase is controlled by at least two methods when DNA replication stalls. The first is ATR-dependent and leads to the well characterized inhibitory phosphorylation of Cdc2; however the second is unknown. Experiments are now underway to explore how this second regulatory pathway functions.
   
   
3. Preventing aging: We have demonstrated that ATR prevents the onset of several age-related phenotypes in mice including hair graying and loss, hunching of the spine (kyphosis) and infertility. Currently, we are exploring the possibility that these and other age-related phenotypes are caused by a loss of specific stem cell populations. Histological and cytometric methods are being employed to further investigate the cause of premature aging in ATR knockout animals.

Lab Personnel:

Amma Asare, Laboratory Manager
Rebecca Chanoux, CAMB Graduate Student
Oren Gilad, Postdoctoral fellow
Yaroslava Ruzankina, Postdoctoral fellow
Karen Urtishak, CAMB Graduate Student
David Schoppy, CAMB Graduate Student
Kevin Smith, CAMB Graduate Student