Postdoctoral Position Available

Michael Brodsky, Ph.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Program in Gene Function and Expression
   Program in Molecular Medicine

Other Affiliation(s):
   Interdisciplinary Graduate Program

Drosophila p53 and DNA Damage-Induced Apoptosis

The overall goal of the lab is to understand how animal cells coordinate cell proliferation and cell death during development. To approach this problem, we are studying the regulation of apoptosis and cell cycle arrest following DNA damage in the fruit fly Drosophila melanogaster. In normal human cells, the p53 transcription factor helps regulate DNA damage-induced apoptosis, partly explaining why p53 is the most frequently mutated gene in human cancer cells. We have shown that a knockout of Drosophila p53 completely eliminates DNA damage-induced transcription and apoptosis (see figure), demonstrating that p53 function has been conserved from insects to mammals. By studying the function of fly p53, we hope to better understand how apoptosis is regulated during normal development and during tumor development.

We are using a combination of genetics, microarrays, and informatics to identify and characterize new regulators and targets of Drosophila p53. Using Affymetrix microarrays, we have identified multiple transcriptional targets of Drosophila p53 including regulators of apoptosis such as reaper and cell-cell signaling molecules such as the Drosophila homolog of Tumor Necrosis Factor. Using genetic analysis, we have identified several genes required for DNA damage-induced apoptosis or cell cycle arrest. Characterization of these genes should provide new insights into how animal tissues respond to DNA damage. As we come to understand how p53 regulates the response to DNA damage, we will explore the mechanisms that determine why only a subset of cells exposed to DNA damage enter the apoptotic pathway and how developmental signals influence that decision.

Drosophila p53 Regulates Irradiation-Induced Apoptosis

Figure

Drosophila wing discs were treated with X-rays and stained for apoptotic cells (green dots). Damage-induced apoptosis is observed in wild type animals (A, B), but not in p53 mutant animals (C, D).

A. Wild type, untreated.
B. Wild type, + X-ray.
C. p53 mutant, untreated.
D. p53 mutant, + X-ray.

Representative Publications

Noyes, M.B., Christensen, R.G., Wakabayashi, A., Stormo, G.D., Brodsky, M.H., Wolfe, S.A. (2008) Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell 133, 1277-1289.

Oikemus, S.R., Queiroz-Machado, J., Lai, K., McGinnis, N., Sunkel, C., Brodsky, M.H. (2006). Epigenetic telomere protection by Drosophila DNA damage response pathways. PLoS Genet. 2, e71.

Meng, X., Brodsky, M.H., Wolfe S.A. (2005). A bacterial one-hybrid system for determining the DNA-binding specificity of transcription factors. Nat Biotechnol. 23, 988-994.

Oikemus, S.R., McGinnis, N., Queiroz-Machado, J., Tukachinsky, H., Takada, S., Sunkel, C.E., Brodsky, M.H. (2004). Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect. Genes Dev. 15, 1850-1861.

Brodsky, M.H., Weinert, B., Tsang, G., Rong, Y.S., McGinnis, N.M., Golic, K.G., Rio, D., Rubin, G.M. (2004). Drosophila Chk2 and p53 regulate multiple DNA repair and apoptotic pathways following DNA damage. Mol. Cell. Biol. 24, 1219-1231.

Abdu, U., Brodsky, M.H., Schupbach, T. (2002). Activation of a meiotic checkpoing during Drosophila oogenesis regulates the translation of Gurken through Chk2/Mnk. Curr. Biol. 12, 1-20.

Rong, Y.S., Titen, S., Xie, H., Golic, M.M., Bastiani, M., Bandyopadhyay, P., Olivera, B.M., Brodsky, M.H., Rubin, G.M., Golic, K.G. (2002). Targeted mutagenesis by homologous recombination in Drosophila melanogaster. Genes Dev. 16, 1568-1581.

Brodsky, M.H., Nordstrom, W., Tsang, G., Kwan, E., Rubin, G.M., Abrams, J.M. (2000). Drosophila p53 binds a damage response element at the reaper locus. Cell 101, 103-113.

Sekelsky, J.J., Brodsky, M.H., Burtis, K.C. (2000). DNA Repair in Drosophila. Insights from the Drosophila genome sequence. J. Cell. Biol. 150, F31-F36.

Brodsky, M.H., Sekelesky, J.J., Tsang, G., Hawley, R.S., Rubin, G.M. (2000). mus304 encodes a novel checkpoint protein required during Drosophila development. Genes Dev. 14, 666-678.

Potential Rotation Projects

We are utilizing a variety of technologies to study p53 regulation and function in Drosophila. These include genetic screens, molecular biology, fluorescence and scanning electron microscopy, tissue culture, RNAi, homologous recombination, and others. Rotation projects in this lab will be determined based on a combination of the student's and PI's interests. Possible projects are listed below:

Project 1: A genetic screen for new regulators of Drosophila p53.

Project 2: Using RNAi and homologous recombination to study regulators of p53.

Project 3: Characterization of p53 activation in Drosophila tissue culture cells by flurescence microscopy, Real-Time PCR, and RNAi.

Project 4: Genetic analysis of Drosophila p53 targets identified in microarray experiments.

Laboratory Personnel

Kuanju Lai, Graduate Student
Laura Lemoine, Graduate Student
Sarah Oikemus, Graduate Student
Atsuya Wakabayashi, Research Assistant
Mary Zona, Research Assistant

Academic Background

Michael Brodsky received his B.A. in Biochemistry from the University of California, Berkeley in 1989 and received his Ph.D. from the Massachusetts Institute of Technology in 1996. From 1996 to 2001, he was a post-doctoral fellow at the University of California, Berkeley where his work was supported by the American Cancer Society and the Howard Hughes Medical Institute. In 2001, Dr. Brodsky joined the faculty of the University of Massachusetts Medical School.

Office: 623
Phone: 508-856-1640
E-mail: Michael.Brodsky@umassmed.edu
Keywords: Oncogenes/tumor suppressors, Chromosome Structure & Dynamics, Apoptosis, DNA Damage and Repair, Organisms - Drosophila

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Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Brodsky for additional details.