Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 19;84(24):4758-4773.e6.
doi: 10.1016/j.molcel.2024.10.024. Epub 2024 Nov 12.

PARP enzyme de novo synthesis of protein-free poly(ADP-ribose)

Marie-France Langelier  1 , Manija Mirhasan  1 , Karine Gilbert  2 , Aleksandr Sverzhinksy  1 , Alexandra Furtos  2 , John M Pascal  3
Affiliations

PARP enzyme de novo synthesis of protein-free poly(ADP-ribose)

Marie-France Langelier et al. Mol Cell. .

Abstract

PARP enzymes transfer ADP-ribose from NAD+ onto proteins as a covalent modification that regulates multiple aspects of cell biology. Here, we identify an undiscovered catalytic activity for human PARP1: de novo generation of free PAR molecules that are not attached to proteins. Free PAR production arises when a molecule of NAD+ or ADP-ribose docks in the PARP1 acceptor site and attaches to an NAD+ molecule bound to the donor site, releasing nicotinamide and initiating ADP-ribose chains that emanate from NAD+/ADP-ribose rather than protein. Free PAR is also produced by human PARP2 and the PARP enzyme Tankyrase. We demonstrate that free PAR in cells is generated mostly by PARP1 de novo synthesis activity rather than by PAR-degrading enzymes PAR glycohydrolase (PARG), ARH3, and TARG1 releasing PAR from protein. The coincident production of free PAR and protein-linked modifications alters models for PAR signaling and broadens the scope of PARP enzyme signaling capacity.

Keywords: ADP-ribose; ARH3; HPF1; PARG; PARP1; PARP2; Parthanatos; TARG1; Tankyrase; poly(ADP-ribose).

PubMed Disclaimer

Conflict of interest statement

Declaration of interests J.M.P. is a co-founder of Hysplex with interests in PARP inhibitor development.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Suskiewicz MJ, Prokhorova E, Rack JGM, and Ahel I (2023). ADP-ribosylation from molecular mechanisms to therapeutic implications at Elsevier B.V, 10.1016/j.cell.2023.08.030. - DOI - PMC - PubMed
    1. Groslambert J, Prokhorova E, and Ahel I (2021). ADP-ribosylation of DNA and RNA. DNA Repair (Amst) 105. 10.1016/j.dnarep.2021.103144. - DOI - PMC - PubMed
    1. Eustermann S, Videler H, Yang JC, Cole PT, Gruszka D, Veprintsev D, and Neuhaus D (2011). The DNA-binding domain of human PARP-1 interacts with DNA single-strand breaks as a monomer through its second zinc finger. J. Mol. Biol 10.1016/j.jmb.2011.01.034. - DOI - PMC - PubMed
    1. Langelier MF, Planck JL, Roy S, and Pascal JM (2011). Crystal structures of poly(ADP-ribose) polymerase-1 (PARP-1) zinc fingers bound to DNA: Structural and functional insights into DNA-dependent PARP-1 activity. J. Biol. Chem 286, 10690–10701. 10.1074/jbc.M110.202507. - DOI - PMC - PubMed
    1. Lonskaya I, Potaman VN, Shlyakhtenko LS, Oussatcheva EA, Lyubchenko YL, and Soldatenkov VA (2005). Regulation of poly(ADP-ribose) polymerase-1 by DNA structure-specific binding. J. Biol. Chem 10.1074/jbc.M413483200. - DOI - PubMed

MeSH terms

LinkOut - more resources