DNA Damage Networks
The goal of the DNA Damage Networks project continues to be development of statistical and physico-chemical models that describe the cellular response to DNA damage at the network and systems biology level.
We are developing experimental and computational methods for monitoring the time-dependent activity of a large number of intracellular protein kinases and signaling molecules, and correlated their activity with the cellular phenotypes of DNA damage-induced cell cycle arrest and re-entry, apoptosis or senescence using quantitative mathematical models. We are applying these measurement and modeling methods to understand how genetic alterations in DNA damage signaling networks, and cross-talk between the EGFR signaling network and the DNA damage signaling network, modify the clinical response of human tumors to currently used genotoxic therapies. Experiments focus on human lymphoma and breast cancer cells, building directly upon our experimental and modeling work in lymphoblastoid and human osteosarcoma cells during the prior funding period. The resulting models of DNA damage-induced signaling and phenotypic will be tested at a variety of scales, including in vitro cell culture systems, murine xenografts, and mouse cancer models. The ultimate goal is to apply these models to predict and optimize the responsiveness of human tumors to DNA damaging therapies and therapy combinations, identify patient- and tumor-specific treatments based on the status of their DNA repair and signal transduction networks, and define new targets and drug combinations that enhance the chemotherapeutic response. The DNA Damage Networks program is closely integrated with the other two core programs in our TCNC, the Mitogenic Networks program and the Migration Networks program through both a shared interest in modulation of tumor cell behavior and therapeutic response by the EGFR signaling pathway, and in the effects of DNA damage on tumor cell proliferation and migration.
Specific Aim 1 - Analysis of breast cancer cell responses to chemotherapeutic agents
Specific Aim 2 - Analysis of lymphoma cell responses to chemotherapeutic agents
Specific Aim 3 - Integrating models for DNA damage response, cell cycle, apoptosis, and ErbB signaling
Fry RC, Svensson JP, Valiathan C, Wang E, Hogan BJ, Bhattacharya S, Bugni JM, Whittaker CA, Samson LD. Genomic predictors of interindividual differences in response to DNA damaging agents. Genes Dev. 2008 Oct 1;22(19):2621-6.
Gardino AK, Smerdon SJ, Yaffe MB. Structural determinants of 14-3-3 binding specificities and regulation of subcellular localization of 14-3-3-ligand complexes: a comparison of the X-ray crystal structures of all human 14-3-3 isoforms. Semin Cancer Biol. 2006 Jun;16(3):173-82.
Janes KA, Reinhardt HC, Yaffe MB. Cytokine-induced signaling networks prioritize dynamic range over signal strength. Cell. 2008 Oct 17;135(2):343-54.
Linding R, Jensen LJ, Ostheimer GJ, van Vugt MA, Jorgensen C, Miron IM, Diella F, Colwill K, Taylor L, Elder K, Metalnikov P, Nguyen V, Pasculescu A, Jin J, Park JG, Samson LD, Woodgett JR, Russell RB, Bork P, Yaffe MB, Pawson T. Systematic discovery of in vivo phosphorylation networks. Cell. 2007 Jun 29;129(7):1415-26.
Linding R, Jensen LJ, Pasculescu A, Olhovsky M, Colwill K, Bork P, Yaffe MB, Pawson T. NetworKIN: a resource for exploring cellular phosphorylation networks. Nucleic Acids Res. 2008 Jan;36(Database issue):D695-9.
Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 2008 Sep 4;455(7209):119-23.
Miller ML, Jensen LJ, Diella F, Jorgensen C, Tinti M, Li L, Hsiung M, Parker SA, Bordeaux J, Sicheritz-Ponten T, Olhovsky M, Pasculescu A, Alexander J, Knapp S, Blom N, Bork P, Li S, Cesareni G, Pawson T, Turk BE, Yaffe MB, Brunak S, Linding R. Linear motif atlas for phosphorylation-dependent signaling. Sci Signal. 2008;1(35):ra2.
Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell. 2007 Feb;11(2):175-89.
Toettcher JE, Loewer A, Ostheimer GJ, Yaffe MB, Tidor B, Lahav G. Distinct mechanisms act in concert to mediate cell cycle arrest. Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):785-90.