Postdoctoral Position in Cancer Biology - Mount Sinai Medical Center, Manhattan, New York
A postdoctoral position is available in the Sam Sidi laboratory, Mount Sinai Medical Center, Manhattan, New York. Mutational damage to genomic DNA both drives the progression of cancer and remains the main mechanism by which we treat the disease (i.e., via radiotherapy or chemotherapy). p53 signaling, which controls DNA repair vs. apoptosis decisions in damaged cells, has long dominated research into how cells respond to DNA injury. However, p53 signaling is almost universally lost during oncogenesis via mutational inactivation of p53 itself or that of its activators or effectors.
To both discover new biology in the DNA damage response and define viable therapeutic strategies in cancer, we have conducted large-scale screens for genetic and chemical suppressors of mutant p53 in zebrafish. These efforts have led to the discovery of novel targets for inhibition in p53mutant cancers (e.g., Chk1 and IRAK1 kinases) and to the identification of an alternative apoptotic axis anchored by the PIDDosome complex (PIDD-RAIDD-caspase-2) which retains full functionality in p53-deficient vertebrate cells (see references 1-5 below).
The successful applicant, an experienced zebrafish researcher with a minimum of basic training in human cell culture biochemistry (e.g., co-IP), will focus on one of several areas currently under investigation:
1. Genetic dissection of the novel, IRAK1-mediated anti-apoptotic response to radiation therapy (ref. 1). Focus on the molecular events upstream, at the level, and downstream of radiation-induced IRAK1 activation. This research is poised to unveil novel drug targets for overcoming resistance to radiotherapy in the million+ patients who fail to respond due to p53 mutation. Such “radiosensitizing” drugs are essentially unavailable and are direly needed in the clinic.
2. Biochemical analysis of a novel, p53-independent molecular switch that decides cell survival or death in response to DNA interstrand crosslinks (ICL). We have recently identified a DNA repair molecule with the ability to sense ICL repair failure and trigger apoptosis as a result (Shah and Sidi, unpublished). This is to our knowledge the first described example of a repair/apoptosis switch, with the potential to define a new paradigm in tumor suppression.
3. Functional analysis of novel regulators of PIDDosome signaling, as recently identified in the lab via RNAi screens and mass spectrometry. Three validated, potentially direct regulators of the complex are available for immediate analysis using combinations of genetics, biochemistry and imaging in zebrafish embryos and cultured human cancer cells (as in refs. 1-4). These projects will both extend our understanding of a novel apoptotic axis in vertebrates, clarify its significance and evolutionary origin, and identify new means to unleash its activity in p53 mutant tumors.
The applicant will take advantage of the vibrant and cutting-edge environment at Mount Sinai and work with our collaborators in world-class bioinformatics, genomics, microscopy, medicinal chemistry and pharmacology departments. The applicant will also participate in new screening efforts in zebrafish for novel drivers and druggable targets in radioresistant and chemoresistant cancer (as in refs. 1 and 5).
Please send cover letter and CV (including a minimum of two reference contacts) tosamuel.sidi@mssm.edu
For more information, please check out our lab websites/media and relevant publications.
http://labs.icahn.mssm.edu/sidilab/ http://psscra.org/winners/samuel-sidi-phd/
http://www.searlescholars.net/person/575 https://www.youtube.com/watch?v=LnyxoxvtcPo
1. Liu PH, et al. An IRAK1-PIN1 signaling axis drives intrinsic tumour resistance to radiation therapy. Nat Cell Biol 21:203-213, 2019.
2. Ando K, et al. NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus. J Cell Biol 216:1795-1810, 2017.
3. Thompson R, et al. An inhibitor of PIDDosome formation. Mol Cell 58:767-779, 2015.
4. Ando K, et al. PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling. Mol Cell 47:681-693, 2012.
5. Sidi S, et al. Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2 and caspase-3. Cell 133:864-877, 2008.