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
Review
. 2018 Dec 17;46(6):1681-1695.
doi: 10.1042/BST20180418. Epub 2018 Nov 12.

PARPs in genome stability and signal transduction: implications for cancer therapy

Luca Palazzo  1 , Ivan Ahel  2
Affiliations
Review

PARPs in genome stability and signal transduction: implications for cancer therapy

Luca Palazzo et al. Biochem Soc Trans. .

Abstract

The poly(ADP-ribose) polymerase (PARP) superfamily of enzymes catalyses the ADP-ribosylation (ADPr) of target proteins by using nicotinamide adenine dinucleotide (NAD+) as a donor. ADPr reactions occur either in the form of attachment of a single ADP-ribose nucleotide unit on target proteins or in the form of ADP-ribose chains, with the latter called poly(ADP-ribosyl)ation. PARPs regulate many cellular processes, including the maintenance of genome stability and signal transduction. In this review, we focus on the PARP family members that possess the ability to modify proteins by poly(ADP-ribosyl)ation, namely PARP1, PARP2, Tankyrase-1, and Tankyrase-2. Here, we detail the cellular functions of PARP1 and PARP2 in the regulation of DNA damage response and describe the function of Tankyrases in Wnt-mediated signal transduction. Furthermore, we discuss how the understanding of these pathways has provided some major breakthroughs in the treatment of human cancer.

Keywords: DNA damage response; PARPs; adenosine diphosphate ribose; cancer; signalling.

PubMed Disclaimer

Conflict of interest statement

The Authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Schematic representation of PARP1-mediated DNA damage repair.
(A) PARP1 in complex with accessory proteins, such as HPF1, is recruited to the DNA damage foci and binds damaged DNA. As a consequence of binding to damaged DNA, PARP1 PARylates serine residues on histones as well as many other factors involved in genome stability. PARylation of histone proteins allows the opening of chromatin structure and a better accessibility of DDR factors, thus facilitating DNA repair. ADP-ribosylation (ADPr) also acts as a scaffold for the recruitment of DDR effector proteins (‘readers’), which are able to recognise and bind the modification. (B) Upon DNA damage repair, the excess of PARP1 automodification induces the release of PARP1 from DNA damage foci and PAR chains are rapidly hydrolysed by ARH3 and PARG. (C) The enzymatic inhibition of PARP1 by PARP inhibitors (PARPi) results in suppression of DNA damage repair and in the trapping of PARP1 to damage foci.
Figure 2.
Figure 2.. Schematic representation of Tankyrase-mediated Wnt/β-catenin signalling.
The canonical Wnt signalling pathway with its major components in the inactive (left) and active (right) state.
See this image and copyright information in PMC

References

    1. Perina D., Mikoč A., Ahel J., C´etković H., Žaja R. and Ahel I. (2014) Distribution of protein poly(ADP-ribosyl)ation systems across all domains of life. DNA Repair 23, 4–16 10.1016/j.dnarep.2014.05.003 - DOI - PMC - PubMed
    1. Palazzo L., Mikoč A. and Ahel I. (2017) ADP-ribosylation: new facets of an ancient modification. FEBS J. 284, 2932–2946 10.1111/febs.14078 - DOI - PMC - PubMed
    1. Cohen M.S. and Chang P. (2018) Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat. Chem. Biol. 14, 236–243 10.1038/nchembio.2568 - DOI - PMC - PubMed
    1. Lüscher B., Bütepage M., Eckei L., Krieg S., Verheugd P. and Shilton B.H. (2018) ADP-ribosylation, a multifaceted posttranslational modification involved in the control of cell physiology in health and disease. Chem. Rev. 118, 1092–1136 10.1021/acs.chemrev.7b00122 - DOI - PubMed
    1. Leung A.K., Vyas S., Rood J.E., Bhutkar A., Sharp P.A. and Chang P. (2011) Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol. Cell 42, 489–499 10.1016/j.molcel.2011.04.015 - DOI - PMC - PubMed

Publication types

MeSH terms

Substances