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【演者】W. Lee Kraus 先生(University of Texas Southwestern Medical Center 教授) 【演題】Role of PARP-1 in Gene E




Poly(ADP-ribose) polymerase 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 and transcription-related 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, as well as its regulation by nuclear NAD+ synthesis, using a variety of biological systems and experimental approaches.

In order to identify the direct and specific targets of PARPs in cells, we have recently established an analog-sensitive PARP mutant approach, where a specific mutation at a highly conserved residue in the catalytic site of PARPs can facilitate ADP-ribosylation using unnatural analogs of NAD+. This allows PARP-specific ADP-ribosylation of substrates, which is suitable for subsequent copper-catalyzed azide-alkyne cycloaddition reactions. Using this approach, we mapped hundreds of sites of ADP-ribosylation for PARPs 1, 2, and 3 across the proteome, as well as thousands of PARP-1-mediated ADP-ribosylation sites across the genome. We found that PARP-1 ADP-ribosylates and inhibits NELF, a protein complex that regulates promoter-proximal pausing by RNA polymerase II (Pol II). Depletion or inhibition of PARP-1, or mutation of the ADP-ribosylation sites on NELF-E, promotes Pol II pausing, providing a clear functional link between PARP-1, ADP-ribosylation, and NELF. This analog-sensitive approach should be broadly applicable across the PARP family, and has the potential to illuminate the protein targets and molecular mechanisms used by individual PARP proteins to mediate their response to cellular signals.

Collectively, Our studies are elucidating the mechanisms by which PARP-1 controls chromatin structure and composition to modulate gene expression.

 Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation. Gibson BA, Zhang Y, Jiang H, Hussey KM, Shrimp JH, Lin H, Schwede F, Yu Y, Kraus WL. Science. 2016 Jul 1;353(6294):45-50

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