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 a poorly understood biopolymer – poly(ADP-ribose) – which is required for life in all multicellular organisms. Mis-regulation of poly(ADP-ribose) is lethal, and appears to be important in human diseases including cancer. A family of 17 enzymes - PARPs – is involved in the formation of poly(ADP-ribose). While most of these enzymes are newly discovered and uncharacterized, several PARPs are up-regulated in cancers. Pharmaceutical companies are currently developing candidate therapeutics targeting the poly(ADP-ribose) polymerases (PARPs). 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. One long-term goal of the lab is to identify mechanistic differences and similarities between physiological and stress-mediated PARP functions. With this information, we hope to determine how PARPs malfunction in human diseases."
Learn more about the Chang lab’s work to better understand a family of proteins called PARPs, and how blocking specific PARPs might be a promising target for cancer therapies by watching this video: "Inside the Lab: Paul Chang, Ph.D."
Dr. Chang is a Career Development Assistant Professor at MIT. He received is Ph.D. from Stanford University in 2002.
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.
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 Biology Nov. 2012.
Schmitt J, Fischer U, Heisel S, Strickfaden H, Backes C, Ruggieri A, Keller A, Chang P, Meese E. Genes Chromosomes Cancer. 2012 May 23
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. Mol Cell. 2011 May 20;42(4):489-99.
Zhu, G., Chang, P., and Lippard, S. J., Recognition of Platinum-DNA Damage by Poly(ADP-Ribose) Polymerase-1. Biochemistry 2010
Chang P, Coughlin M, Mitchison TJ. Interaction between Poly(ADP-ribose) and NuMA contributes to mitotic spindle pole assembly. Mol Biol Cell. 2009 Nov;20(21):4575-85
Chang P, Coughlin M, Mitchison TJ. Tankyrase-1 polymerization of poly(ADP-ribose) is required for spindle structure and function. Nature Cell Bio. 2005 Nov; 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. 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 Bio. 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 Bio. 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