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Role of PARPs in the Metabolic Regulation of Chromatin Structure and Gene Expression

Southwestern Medical Center, Dallas, États-Unis

vendredi 02 juin 2017 - 14h00 - Auditorium, IGBMC
Invité(e) par Equipe L. Tora

ADP-ribosylation is a reversible post-translational modification of proteins resulting in the covalent attachment of a single ADP-ribose (ADPR) unit [i.e., mono(ADP-ribose), or MAR] or polymers of ADPR units [i.e., poly(ADP-ribose), or PAR] on a variety of amino acid residues on target proteins (most commonly glutamate, aspartate, and lysine residues).  This modification is mediated by a diverse group of ADP-ribosyl transferase enzymes, including the “PARP” family, that use ADP-ribose units derived from β-NAD+ to catalyze the ADP-ribosylation reactions.  The PARP family consists of 17 members, including both monoenzymes (MARTs) and polyenzymes (PARPs), that have distinct structural domains, activities, subcellular localizations, and functions.  The nuclear PARPs, such as the polyenzymes PARP-1, PARP-2, and Tankyrases (PARP-5) and the monoenzyme PARP-3, are the most widely studied enzymes in the PARP family.  Although PARPs 1, 2, and 3 have been studies primarily in the context of DNA repair, my lab has been investigating their roles in the regulation of gene expression, with a focus on PARP-1.

            PARP-1 is a multifunctional regulator of chromatin and transcription that controls patterns of gene expression in a variety of cellular systems.  PARP-1 has a number of functional domains that confer biochemical activities well suited for chromatin-dependent functions, including a DNA binding domain and a catalytic domain.  The DNA binding activity of PARP-1 allows it to bind specifically to nucleosomes in open regions of chromatin, whereas the enzymatic activity catalyzes the production of poly(ADP-ribose) chains on target proteins using NAD+ as a donor of ADP-ribose units.  We have been studying the role of PARP-1 in chromatin-mediated gene regulation using a variety of biological systems, including (1) TNFa-stimulated, NF-kB-dependent pro-inflammatory responses in cardiomyocytes, (2) insulin-, glucocorticoid-, and cAMP-stimulated differentiation of pre-adipocytes, (3) interferon γ-stimulated, STAT-1-dependent pro-inflammatory responses in macrophages, (4) estrogen-stimulated, ERα-dependent mitogenic responses in breast cancer cells, and (5) pluriopotency and lineage specification in embryonic stem cells. 

            Using a combination of biochemical, molecular, cell-based, proteomic, chemical genetic, and genomic assays, we have (1) defined the mode of nucleosome binding by PARP-1, (2) identified hundreds of specific sites of ADP-ribosylation on PARP-1 target proteins, (3) determined the genomic location of PARP-1 at nucleosome resolution, (4) explored the role of PARP-1 in signal-regulated transcriptional responses, (5) determined how PARP-1 regulates histone-modifying enzymes to establish permissive chromatin environments, and (6) uncovered a role for nicotinamide mononucleotide adenylyltransferase (NMNAT-1), a nuclear NAD+ synthase, in determining PARP-1 activity at promoters.  These studies have begun to elucidate the mechanisms by which PARP-1 controls chromatin structure and composition to modulate gene expression in important physiological systems.

W. Lee Kraus Laboratory of Signaling and Gene Expression, Green Center for Reproductive Biology Sciences and Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390.

The PARP-related work in the Kraus lab is funded by the NIH/NIDDK (R01 DK069710), the Cancer Prevention and Research Institute of Texas (RP160319), and the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment.


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