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24 results on '"Steffen, Jamin D."'

6. Structural basis for allosteric PARP-1 retention on DNA breaks

Author

Zandarashvili, Levani, primary, Langelier, Marie-France, additional, Velagapudi, Uday Kiran, additional, Hancock, Mark A., additional, Steffen, Jamin D., additional, Billur, Ramya, additional, Hannan, Zain M., additional, Wicks, Andrew J., additional, Krastev, Dragomir B., additional, Pettitt, Stephen J., additional, Lord, Christopher J., additional, Talele, Tanaji T., additional, Pascal, John M., additional, and Black, Ben E., additional

Published
2020
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15. PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain

Author

Dawicki-McKenna, Jennine M., primary, Langelier, Marie-France, additional, DeNizio, Jamie E., additional, Riccio, Amanda A., additional, Cao, Connie D., additional, Karch, Kelly R., additional, McCauley, Michael, additional, Steffen, Jamin D., additional, Black, Ben E., additional, and Pascal, John M., additional

Published
2015
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16. 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

Author

Patel, Maulik R., primary, Bhatt, Aaditya, additional, Steffen, Jamin D., additional, Chergui, Adel, additional, Murai, Junko, additional, Pommier, Yves, additional, Pascal, John M., additional, Trombetta, Louis D., additional, Fronczek, Frank R., additional, and Talele, Tanaji T., additional

Published
2014
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23. Discovery and Structure–Activity Relationships of Modified Salicylanilides as Cell Permeable Inhibitors of Poly(ADP-ribose) Glycohydrolase (PARG).

Author

Steffen, Jamin D., Coyle, Donna L., Damodaran, Komath, Beroza, Paul, and Jacobson, Myron K.

Subjects
*SALICYLANILIDES, *CELL permeability, *ADENOSINE diphosphate, *HYDROLASES, *CELL death, *DRUG development, *SQUAMOUS cell carcinoma, *DRUG metabolism
Abstract

The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure–activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development. [ABSTRACT FROM AUTHOR]

Published
2011
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24. Purification of DNA Damage-Dependent PARPs from E. coli for Structural and Biochemical Analysis.

Author

Langelier MF, Steffen JD, Riccio AA, McCauley M, and Pascal JM

Subjects
Animals, Chromatography, Affinity, DNA Damage drug effects, Escherichia coli enzymology, Humans, Poly (ADP-Ribose) Polymerase-1 metabolism, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerases isolation & purification, Poly(ADP-ribose) Polymerases metabolism, DNA Damage genetics, Poly (ADP-Ribose) Polymerase-1 isolation & purification
Abstract

Human PARP-1, PARP-2, and PARP-3 are key players in the cellular response to DNA damage, during which their catalytic activities are acutely stimulated through interaction with DNA strand breaks. There are also roles for these PARPs outside of the DNA damage response, most notably for PARP-1 and PARP-2 in the regulation of gene expression. Here, we describe a general method to express and purify these DNA damage-dependent PARPs from E. coli cells for use in biochemical assays and for structural and functional analysis. The procedure allows for robust production of PARP enzymes that are free of contaminant DNA that can interfere with downstream analysis. The described protocols have been updated from our earlier reported methods, most importantly to introduce PARP inhibitors in the production scheme to cope with enzyme toxicity that can compromise the yield of purified protein.

Published
2017
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