Ph.D. 2002, Stanford University
KI Research Areas of Focus:
Ph.D. 2002, Stanford University
KI Research Areas of Focus:
"Our laboratory is focused on understanding the function of the Poly(ADP-ribose) Polymerase family of proteins or PARPs. PARPs generate ADP-ribose modifications onto target proteins using NAD+ as substrate. One of the key functions of PARPs is to mediate cellular stress responses such as DNA damage, and Heat shock. It is in the context of DNA damage repair that PARP inhibition has received so much attention as a potential avenue for therapeutic inhibition of cancers."
Recently the lab identified two new stress functions for PARPs, regulation of the unfolded protein response, known to be upregulated in cancers, and a target of therapeutic inhibition; and the cytoplasmic stress response, shown to be activated in tumors. It is currently examining the detailed mechanism of PARP function in these stress pathways and investigating possible avenues for their therapeutic inhibition.
Poly(ADP-ribose) is a poorly understood biopolymer and post-translational modification required for life in all multicellular organisms. While primarily known for its role in DNA damage repair, it functions in many essential cellular processes such as cell division and cell cycle progression as well as transcriptional and translational regulation. Poly(ADP-ribose) is polymerized onto acceptor proteins by a family of 17 PARPs using NAD+ as substrate. The majority of these are newly identified and uncharacterized. Several are up-regulated in cancers. Mis-regulation of poly(ADP-ribose) is lethal, and appears to be important in human diseases such as cancers, prompting pharma-ceutical companies to develop candidate therapeutics targeting the poly(ADP-ribose) polymerases (PARPs).
What makes poly(ADP-ribose) so interesting is that it acts as both a traditional protein modification, like phosphorylation or ubiquitination, and a macromolecule with chemical similarities to nucleic acids and carbohydrates. Like these other polymers, poly(ADP-ribose) binds specific proteins, however due to its rapid turnover dynamics, protein binding can be regulated in time and space making poly(ADP-ribose) an ideal mediator of dynamic protein localization.
To better understand poly(ADP-ribose) and PARPs, we are taking a systems-level approach by first determining where, when and how poly(ADP-ribose) and PARPs function in the cell. We have started by characterizing the localization and function of each of the 17 PARPs simultaneously using a combination of antibody staining, long-term imaging of GFP fusions, and RNAi. These preliminary experiments have identified several PARPs as essential for somatic cell function and localized the majority of the PARP proteins to the cytoplasm, membranes and vesicles during interphase, and to the mitotic spindle during mitosis. To better understand and identify the biological pathways of PARP function, and to identify functionally conserved mechanisms, we are identifying all PARP binding proteins, and poly(ADP-ribose) acceptor and binding proteins using biochemical approaches. Finally, to understand when PARPs are active, we are designing ways to monitor PARP activity in cells real time using fluorescence microscopy.
Some of the best understood poly(ADP-ribose) functions occur as a response to cell stresses such as DNA damage, and apoptosis. In collaboration with Phil Sharp's lab at MIT, we have identified a poly(ADP-ribose) and PARP requirement in new stress pathways, and have identified specific PARPs that function in these stress responses. Our lab is continuing to identify new stress pathways in which PARPs function, and, with our library of 17 PARP clones and siRNAs, have revisited functions for other PARPs in DNA damage and apoptosis. One long term goal of the lab is to identify mechanistic differences and similarities between physiological and stresss mediated PARP functions. With this information, we hope to determine how PARPs malfunction in human diseases.
Vyas, S. Chesarone-Cataldo M, Todorova T, Huang YH, Chang P. A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nature Communications 2013 4:2240
Vyas S, Chang P. Dual roles for PARP1 during heat shock: transcriptional activator and posttranscriptional inhibitor of gene expression. Molecular Cell. 2013 Jan 10;49(1):1-3
Jwa M, Chang P. PARP-16 is a tail-anchored endoplasmic reticulum protein required for the PERK and IRE1alpha-mediated unfolded protein response. Nature Cell Biol. 2012 Nov;14(11):1223-30
Schmitt J, Fischer U, Heisel S, Strickfaden H, Backes C, Ruggieri A, Keller A, Chang P, Meese E. GAS41 amplification results in overexpression of a new spindle pole protein. Genes Chromosomes Cancer. 2012 May 23: 10.1002/gcc.21971.
Leung AK, Todorova T, Ando Y, Chang P. Poly(ADP-ribose) regulates post-transcriptional processes in the cytoplasm. RNA Biol. 2012 May 1;9(5)
Rood JE, Leung AK, Chang P. Methods for purification of proteins associated with cellular poly(ADP-ribose) and PARP-specific poly(ADP-ribose). Methods Mol Biol. 2011;780:153-64
Leung AK, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P. Poly(ADP-Ribose) regulates stress responses and microRNA activity in the cytoplasm. Molecular Cell. 2011 May 20;42(4):489-99.
Zhu G, Chang P, Lippard SJ. Recognition of platinum-DNA damage by poly(ADP-ribose) polymerase-1. Biochemistry. 2010 Jul 27;49(29):6177-83.
Chang P, Coughlin M, Mitchison TJ. Interaction between Poly(ADP-ribose) and NuMA contributes to mitotic spindle pole assembly. Molecular Biology of the Cell 2009 Sep; 10(1091)
Chang P, Coughlin M, Mitchison TJ. Tankyrase-1 polymerization of poly(ADP-ribose) is required for spindle structure and function. Nature Cell Biology 2005 ov;7(11):1133-9.
Chang P, Jacobson MK, Mitchison TJ. Poly(ADP-ribose) is required for spindle assembly and structure. Nature 2004 Dec 2;432(7017):645-9.
Louie RK, Bahmanyar S, Siemers KA, Votin V, Chang P, Stearns T, Nelson WJ, Barth AI. Adenomatous polyposis coli and EB1 localize in close proximity of the mother centriole and EB1 is a functional component of centrosomes. J Cell Science 2004 Mar 1;117(Pt 7):1117-28.
Chang P, Giddings TH, Winey M, Stearns T. Epsilon-tubulin is required for centriole duplication and microtubule organization. Nature Cell Biology 2003 Jan;5(1):71-6.
Chang P, Stearns T. Delta-tubulin and epsilon-tubulin: two new human centrosomal tubulins reveal new aspects of centrosome structure and function. Nature Cell Biology 2000 Jan;2(1):30-5.
Weisblat DA, Huang FZ, Isaksen DE, Liu NJ, Chang P. The other side of the embryo: an appreciation of the non-D quadrants in leech embryos. Current Topics Developmental Biology 1999;46:105-32.