Cargando…

HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase

Poly(ADP-ribose) polymerase 1 (PARP1) is an important player in the response to DNA damage. Recently, Histone PARylation Factor (HPF1) was shown to be a critical modulator of the activity of PARP1 by facilitating PARylation of histones and redirecting the target amino acid specificity from acidic to...

Descripción completa

Detalles Bibliográficos
Autores principales: Rudolph, Johannes, Roberts, Genevieve, Muthurajan, Uma M, Luger, Karolin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012059/
https://www.ncbi.nlm.nih.gov/pubmed/33683197
http://dx.doi.org/10.7554/eLife.65773
_version_ 1783673307985346560
author Rudolph, Johannes
Roberts, Genevieve
Muthurajan, Uma M
Luger, Karolin
author_facet Rudolph, Johannes
Roberts, Genevieve
Muthurajan, Uma M
Luger, Karolin
author_sort Rudolph, Johannes
collection PubMed
description Poly(ADP-ribose) polymerase 1 (PARP1) is an important player in the response to DNA damage. Recently, Histone PARylation Factor (HPF1) was shown to be a critical modulator of the activity of PARP1 by facilitating PARylation of histones and redirecting the target amino acid specificity from acidic to serine residues. Here, we investigate the mechanism and specific consequences of HPF1-mediated PARylation using nucleosomes as both activators and substrates for PARP1. HPF1 provides that catalytic base Glu284 to substantially redirect PARylation by PARP1 such that the histones in nucleosomes become the primary recipients of PAR chains. Surprisingly, HPF1 partitions most of the reaction product to free ADP-ribose (ADPR), resulting in much shorter PAR chains compared to reactions in the absence of HPF1. This HPF1-mediated switch from polymerase to hydrolase has important implications for the PARP1-mediated response to DNA damage and raises interesting new questions about the role of intracellular ADPR and depletion of NAD(+).
format Online
Article
Text
id pubmed-8012059
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-80120592021-04-02 HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase Rudolph, Johannes Roberts, Genevieve Muthurajan, Uma M Luger, Karolin eLife Biochemistry and Chemical Biology Poly(ADP-ribose) polymerase 1 (PARP1) is an important player in the response to DNA damage. Recently, Histone PARylation Factor (HPF1) was shown to be a critical modulator of the activity of PARP1 by facilitating PARylation of histones and redirecting the target amino acid specificity from acidic to serine residues. Here, we investigate the mechanism and specific consequences of HPF1-mediated PARylation using nucleosomes as both activators and substrates for PARP1. HPF1 provides that catalytic base Glu284 to substantially redirect PARylation by PARP1 such that the histones in nucleosomes become the primary recipients of PAR chains. Surprisingly, HPF1 partitions most of the reaction product to free ADP-ribose (ADPR), resulting in much shorter PAR chains compared to reactions in the absence of HPF1. This HPF1-mediated switch from polymerase to hydrolase has important implications for the PARP1-mediated response to DNA damage and raises interesting new questions about the role of intracellular ADPR and depletion of NAD(+). eLife Sciences Publications, Ltd 2021-03-08 /pmc/articles/PMC8012059/ /pubmed/33683197 http://dx.doi.org/10.7554/eLife.65773 Text en © 2021, Rudolph et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Rudolph, Johannes
Roberts, Genevieve
Muthurajan, Uma M
Luger, Karolin
HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase
title HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase
title_full HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase
title_fullStr HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase
title_full_unstemmed HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase
title_short HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase
title_sort hpf1 and nucleosomes mediate a dramatic switch in activity of parp1 from polymerase to hydrolase
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012059/
https://www.ncbi.nlm.nih.gov/pubmed/33683197
http://dx.doi.org/10.7554/eLife.65773
work_keys_str_mv AT rudolphjohannes hpf1andnucleosomesmediateadramaticswitchinactivityofparp1frompolymerasetohydrolase
AT robertsgenevieve hpf1andnucleosomesmediateadramaticswitchinactivityofparp1frompolymerasetohydrolase
AT muthurajanumam hpf1andnucleosomesmediateadramaticswitchinactivityofparp1frompolymerasetohydrolase
AT lugerkarolin hpf1andnucleosomesmediateadramaticswitchinactivityofparp1frompolymerasetohydrolase