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Faculty Affairs: Faculty Interests Database John M Pascal, PhD

Biochemistry & Molecular Biology
Thomas Jefferson University
Jefferson Medical College
Associate Professor
Mailing Address Contact Information
233 South 10th Street, BLSB 804
Philadelphia, Pennsylvania 19107
United States
Phone: 215-503-4596
Fax: 215-923-2117
John.Pascal@Jefferson.edu
Personal Web Site
Qualifications
Ph.D., University of Texas at Austin, 2000
Expertise and Research Interests
We study protein structure and function to understand how cells replicate and repair DNA, and how the integrity of the genome is preserved during these processes. A major objective is to determine the three-dimensional structure of proteins to visualize how their architecture and design are related to their functions in the cell. We are particularly interested in the proteins that detect and respond to breaks in the structure of DNA, a common and potentially lethal form of DNA damage. 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.
Keywords
Structural cell biology; protein structure and function; macromolecular x-ray crystallography; DNA damage detection and repair; DNA replication; chromosomal metabolism and genome maintenance; biochemistry; biophysics; poly(ADP- ribose) polymerases (PARPs); DNA ligases; NAD metabolism; ADP ribosylation reactions
Publications
  • Recent Publications
  • 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, 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.
  • Chan TO, Zhang J, Rodeck U, Pascal JM, Armen RS, Spring M, Dumitru CD, Myers V, Li X, Cheung
  • JY, Feldman AM. (2011) Resistance of Akt kinases to dephosphorylation through ATP-dependent
  • conformational plasticity. PNAS 108, E1120-7.
  • Liu C, Sanders JM, Pascal JM, Hou YM. (2012) Adaptation to tRNA acceptor stem structure by flexible
  • adjustment in the catalytic domain of class I tRNA synthetases. RNA 18:213-21.
  • Zhang M, Abrams C, Wang L, Gizzi A, He L, Lin R, Chen Y, Loll PJ, Pascal JM, Zhang J-f (2012)
  • Structural basis for calmodulin as a dynamic calcium sensor. Structure 20, 911-23.
  • 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.
  • **Featured in an editors choice column in Science and in Nature Reviews Clinical Oncology, and a News
  • and Views in Nature Structure Molecular Biology.
  • 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.
  • Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL, Liu F, Planck JL, Ravindranathan
  • P, Chinnaiyan AM, McCue P, Gomella LG, Raj GV, Dicker AP, Brody JR, Pascal JM, Centenera MM, Butler
  • LM, Tilley WD, Feng FY, Knudsen KE. (2012) Dual roles of PARP-1 promote cancer growth and progression.
  • Cancer Discovery 2, 1134-49.
  • Zhang M, Pascal JM, Zhang JF. (2013) Unstructured to structured transition of an intrinsically disordered
  • protein peptide in coupling Ca2+-sensing and SK channel activation. PNAS 110, 4828-33.
  • 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, 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. (designated a Breakthrough Article)
  • Patel MR, Bhatt A, Steffen JD, Chergui A, Murai J, Pommier Y, Pascal JM, Trombetta LD, Fronczek
  • FR, Talele TT. (2014) Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-
  • carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-
  • ribose)polymerase-1 Inhibitors. Journal of Medicinal Chemistry [Epub ahead of print] PMID: 24922587.
  • Zhang M, Meng X-Y, Cui M, Pascal JM, Logothetis D, and Zhang J-f. (2014) Modulation of PIP2
  • sensitivity of the CaM-SK channel complex through selective phosphorylation. Nature Chemical Biology (in
  • the press).

Last Updated by John Pascal, PhD: Monday, July 2, 2012 11:15:46 AM

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