John M. Pascal

Professor

Photo_JPascal

Contact Informations

Département de biochimie
Faculté de médecine
Université de Montréal
Pavillon Roger-Gaudry, room D-347
C.P. 6128, Succ. Centre-ville
Montréal (Québec)
H3C 3J7

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P 514 343-6111 ext. 4890
F 514 343-2110
john.pascal@umontreal.ca
Web

Themes

  • Structural Cell Biology
  • Macromolecular X-ray Crystallography
  • Mechanisms of DNA Replication and Repair
  • Function and Regulation of Poly(ADP-Ribose) Polymerases (PARPs)

We study protein structure and function to understand the molecular details of the macromolecules that carry out fundamental cellular processes. By advancing our knowledge of protein function, we can better understand how specific protein deficiencies lead to human disease, and we can potentially identify new ways to regulate protein activity for therapeutic treatments. A major objective of our work is to determine the three-dimensional structure of proteins to visualize how their architecture and design are related to their functions in the cell. X-ray crystallography is our primary tool for determining the structures of proteins and protein-DNA complexes. We also use other biophysical techniques, biochemical tools, and cell biological approaches to assay protein structure and function.

Publications

  • Riccio AA, Cingolani G, Pascal JM. (2016) PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DN damage. Nucleic Acids Research 44, 1691-702.
  • Dawicki-McKenna JM, Langelier MF, DeNizio JE, Riccio AA, Cao CD, Karch KR, McCauley M, Steffen JD, Black BE, Pascal JM. (2015) PARP-1 activation requires local unfolding of an autoinhibitory domain. Molecular Cell 60, 755-68.
  • Eustermann S, Wu WF, Langelier MF, Yang JC, Easton LE, Riccio AA, Pascal JM, Neuhaus D. (2015) Structural basis of detection and signaling of DNA single-strand breaks by human PARP-1. Molecular Cell 60, 742-54.
  • Langelier MF, Riccio AA, Pascal JM. (2014) PARP-2 and PARP-3 are selectively activated by 5’ phosphorylated DNA breaks through an allosteric regulatory mechanism shared with PARP-1. Nucleic Acids Research 42, 7762-75.
  • Steffen JD, Tholey RM, Langelier MF, Planck JL, Schiewer MJ, Lal S, Bildzukewicz NA, Yeo CJ, Knudsen KE, Brody JR, Pascal JM. (2014) Targeting PARP-1 allosteric regulation offers therapeutic potential against cancer. Cancer Research 74, 31-7.
  • Langelier MF, Pascal JM. (2013) PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis. Current Opinion in Structural Biology 23, 134-43.
  • Langelier MF, Planck JL, Roy S, Pascal JM (2012) Structural basis for DNA-dependent poly(ADP-ribosyl)ation by human PARP-1. Science 336, 728-32.
  • Zhang M, Pascal JM, Schumann M, Armen RS, Zhang J-f (2012) Identification of the functional binding pocket for compounds targeting small-conductance Ca2+-activated potassium channels. Nature Communications 3, 1021.
  • Langelier M-F, Planck JL, Roy S, Pascal JM (2011) Crystal structures of poly(ADP-ribose) polymerase-1 (PARP-1) zinc fingers bound to DNA: structural and functional insights into DNA-dependent PARP-1 activity. Journal of Biological Chemistry 286, 10690-701.
  • Langelier M-F, Ruhl DD, Planck JL, Kraus WL, Pascal JM (2010) The Zn3 domain of human poly(ADP-ribose) polymerase-1 (PARP-1) functions in both DNA-dependent poly(ADP-ribose) synthesis activity and chromatin compaction. Journal of Biological Chemistry 285, 18877-87.
  • Langelier M-F, Servent KM, Rogers EE, Pascal JM (2008) A third zinc binding domain in Poly(ADPribose) polymerase 1 coordinates DNA-dependent enzyme activation. Journal of Biological Chemistry 283, 4105-14.