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Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation
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Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation
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Journal Article
Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation
2016
Overview
Poly[adenosine diphosphate (ADP)—ribose] polymerases (PARPs) are a family of enzymes that modulate diverse biological processes through covalent transfer of ADP-ribose from the oxidized form of nicotinamide adenine dinucleotide (NAD⁺) onto substrate proteins. Here we report a robust NAD⁺ analog—sensitive approach for PARPs, which allows PARP-specific ADP-ribosylation of substrates that is suitable for subsequent coppercatalyzed 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 negative elongation factor (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 ADP-ribosylated proteome and the molecular mechanisms used by individual PARPs to mediate their responses to cellular signals.
Publisher
American Association for the Advancement of Science,The American Association for the Advancement of Science
Subject
/ Adenosine Diphosphate - chemistry
/ Animals
/ Cell Cycle Proteins - metabolism
/ Enzymes
/ Genomes
/ Humans
/ Mice
/ Pol II
/ Poly (ADP-Ribose) Polymerase-1
/ Poly(ADP-ribose) Polymerases - genetics
/ Poly(ADP-ribose) Polymerases - metabolism
/ Positive Transcriptional Elongation Factor B - metabolism
/ Proteins
/ RNA Polymerase II - metabolism
