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PARP14 is a writer, reader, and eraser of mono-ADP-ribosylation

Torretta, Archimede LU ; Chatzicharalampous, Constantinos LU orcid ; Ebenwaldner, Carmen LU and Schüler, Herwig LU orcid (2023) In The Journal of biological chemistry 299(9).
Abstract

PARP14/BAL2 is a large multidomain enzyme involved in signaling pathways with relevance to cancer, inflammation, and infection. Inhibition of its mono-ADP-ribosylating PARP homology domain and its three ADP-ribosyl binding macro domains has been regarded as a potential means of therapeutic intervention. Macrodomains-2 and -3 are known to stably bind to ADP-ribosylated target proteins, but the function of macrodomain-1 has remained somewhat elusive. Here, we used biochemical assays of ADP-ribosylation levels to characterize PARP14 macrodomain-1 and the homologous macrodomain-1 of PARP9. Our results show that both macrodomains display an ADP-ribosyl glycohydrolase activity that is not directed toward specific protein side chains. PARP14... (More)

PARP14/BAL2 is a large multidomain enzyme involved in signaling pathways with relevance to cancer, inflammation, and infection. Inhibition of its mono-ADP-ribosylating PARP homology domain and its three ADP-ribosyl binding macro domains has been regarded as a potential means of therapeutic intervention. Macrodomains-2 and -3 are known to stably bind to ADP-ribosylated target proteins, but the function of macrodomain-1 has remained somewhat elusive. Here, we used biochemical assays of ADP-ribosylation levels to characterize PARP14 macrodomain-1 and the homologous macrodomain-1 of PARP9. Our results show that both macrodomains display an ADP-ribosyl glycohydrolase activity that is not directed toward specific protein side chains. PARP14 macrodomain-1 is unable to degrade poly(ADP-ribose), the enzymatic product of PARP1. The F926A mutation of PARP14 and the F244A mutation of PARP9 strongly reduced ADP-ribosyl glycohydrolase activity of the respective macrodomains, suggesting mechanistic homology to the Mac1 domain of the SARS-CoV-2 Nsp3 protein. This study adds two new enzymes to the previously known six human ADP-ribosyl glycohydrolases. Our results have key implications for how PARP14 and PARP9 will be studied and how their functions will be understood.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of biological chemistry
volume
299
issue
9
article number
105096
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • scopus:85168310910
  • pmid:37507011
ISSN
1083-351X
DOI
10.1016/j.jbc.2023.105096
project
Structure-function relationship in ADP-ribosyl transferases
language
English
LU publication?
yes
id
099ead83-dac1-4379-b152-d853a54b9aa3
date added to LUP
2023-09-28 11:34:46
date last changed
2024-04-19 01:47:04
@article{099ead83-dac1-4379-b152-d853a54b9aa3,
  abstract     = {{<p>PARP14/BAL2 is a large multidomain enzyme involved in signaling pathways with relevance to cancer, inflammation, and infection. Inhibition of its mono-ADP-ribosylating PARP homology domain and its three ADP-ribosyl binding macro domains has been regarded as a potential means of therapeutic intervention. Macrodomains-2 and -3 are known to stably bind to ADP-ribosylated target proteins, but the function of macrodomain-1 has remained somewhat elusive. Here, we used biochemical assays of ADP-ribosylation levels to characterize PARP14 macrodomain-1 and the homologous macrodomain-1 of PARP9. Our results show that both macrodomains display an ADP-ribosyl glycohydrolase activity that is not directed toward specific protein side chains. PARP14 macrodomain-1 is unable to degrade poly(ADP-ribose), the enzymatic product of PARP1. The F926A mutation of PARP14 and the F244A mutation of PARP9 strongly reduced ADP-ribosyl glycohydrolase activity of the respective macrodomains, suggesting mechanistic homology to the Mac1 domain of the SARS-CoV-2 Nsp3 protein. This study adds two new enzymes to the previously known six human ADP-ribosyl glycohydrolases. Our results have key implications for how PARP14 and PARP9 will be studied and how their functions will be understood.</p>}},
  author       = {{Torretta, Archimede and Chatzicharalampous, Constantinos and Ebenwaldner, Carmen and Schüler, Herwig}},
  issn         = {{1083-351X}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{9}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{The Journal of biological chemistry}},
  title        = {{PARP14 is a writer, reader, and eraser of mono-ADP-ribosylation}},
  url          = {{http://dx.doi.org/10.1016/j.jbc.2023.105096}},
  doi          = {{10.1016/j.jbc.2023.105096}},
  volume       = {{299}},
  year         = {{2023}},
}