Date: 6 October 2016, Thursday
Time: 11:00AM – 12:00PM
Venue: Level 3, IMCB Seminar Room 3-46, Proteos, Biopolis
The PIDDosome: a Caspase-Activation Platform at the Crossroads of Genome Surveillance Pathways
by Dr. Samuel Sidi, Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, USA
The PIDDosome—PIDD-RAIDD-caspase-2 complex—is a proapoptotic caspase-activation platform whose significance has remained unclear since its biochemical isolation by Tschopp and colleagues in the mid 2000’s. High rates of aneuploidy in Caspase-2 null mice suggest a critical role in genome maintenance. In contrast to the apoptosome (cytc-APAF1-caspase-9) and DISC (FAS-FADD-caspase-8), however, the stimuli and molecules that control PIDDosome formation remain largely unknown. We previously identified the DNA damage response kinases, Chk1 and ATM, and the mitotic checkpoint effector, BubR1, as direct regulators of PIDDosome assembly and function in response to double-strand DNA breaks (DSBs). Here we discuss two novel regulators of PIDDosome formation, identified in a proteomics screen. 1) The DNA repair protein, FANCI, acting in a non-canonical role independent of FANCD2 to stimulate PIDDosome formation in response to interstrand DNA crosslinks. And, 2) The nucleolar phosphoprotein, nucleophosmin/NPM1, a critical but poorly understood tumor suppressor in AML, which directs PIDDosome formation in the nucleolus in response to DSBs.
Biography: Samuel Sidi is an Assistant Professor of Medicine and Oncological Sciences at the Icahn School of Medicine at Mount Sinai, NYC. Originally from Paris, Dr Sidi completed his graduate studies at the Max-Planck Institute in Tubingen and the Ecole Normale Superieure (Paris VI University), graduating in 2004. His Ph.D. thesis focused on a large-scale screen for mutations affecting balance in zebrafish, which identified ion channels essential for inner ear function. Dr. Sidi conducted his postdoctoral studies with A. Thomas Look at the Dana-Farber Cancer Institute, where he developed zebrafish screening platforms for drug and target discovery in radio/chemo-resistant cancer. Dr Sidi’s current research focuses on the signaling pathways unveiled by these screens – including the PIDDosome apoptotic pathway triggered by Chk1 inhibitors – exploring their significance and therapeutic potential. Dr. Sidi has been supported by the NIH/NCI, the Claudia Adams Barr Foundation, JJR Foundation, Pershing Square Sohn Alliance and Searle Scholars Program.
