Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jun;34(26):3349-56.
doi: 10.1038/onc.2014.295. Epub 2014 Sep 15.

The role of poly(ADP-ribosyl)ation in DNA damage response and cancer chemotherapy

M Li  1 , X Yu  2
Affiliations
Review

The role of poly(ADP-ribosyl)ation in DNA damage response and cancer chemotherapy

M Li et al. Oncogene. 2015 Jun.

Abstract

DNA damage is a deleterious threat, but occurs daily in all types of cells. In response to DNA damage, poly(ADP-ribosyl)ation, a unique post-translational modification, is immediately catalyzed by poly(ADP-ribose) polymerases (PARPs) at DNA lesions, which facilitates DNA damage repair. Recent studies suggest that poly(ADP-ribosyl)ation is one of the first steps of cellular DNA damage response and governs early DNA damage response pathways. Suppression of DNA damage-induced poly(ADP-ribosyl)ation by PARP inhibitors impairs early DNA damage response events. Moreover, PARP inhibitors are emerging as anti-cancer drugs in phase III clinical trials for BRCA-deficient tumors. In this review, we discuss recent findings on poly(ADP-ribosyl)ation in DNA damage response as well as the molecular mechanism by which PARP inhibitors selectively kill tumor cells with BRCA mutations.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Sketch of poly(ADP-ribosyl)ation
With NAD+ as the donor, PARPs mediate the genotoxic stress-dependent poly(ADP-ribosyl)ation. ADP-ribose residues are covalently linked to the side chains of arginine, lysine, aspartate, or glutamate residues of acceptor proteins. Glycosidic ribose-ribose 1′–2′ bonds between ADP-ribose units generate both linear and branched polymers. The chain length of PAR is heterogeneous, which can reach up to 200 ADP-ribose units, with 20–50 units in each branch.
Figure 2
Figure 2. Domain architecture of human PARP1
Human PARP1 contains 1014 residues of amino acid with the molecular weight of 116 kDa. N-terminal three zinc finger motifs (Zn1-3) recognize SSBs and DSBs, which induces the conformational changes of the Tryptophan-glycine-arginine rich (WGR) and Catalytic domains and activates the enzymatic activity of PARP1.
Figure 3
Figure 3. Poly(ADP-ribosyl)ation functions as a sensor for activating DNA damage response
In response to SSBs and DSBs, massive PAR is rapidly generated by PARPs and jumpstarts DNA damage response. In the NER pathway for SSB repair, PAR mediates the recruitment of DDB2 and ALC1. In the BER pathway, PAR targets PNKP, APTX, XRCC1 and APLF to DNA lesions for the subsequent repair. In NHEJ pathway for DSB repair, PAR mediates the recruitment of the Ligase IV -XRCC4 complex. In HR pathway for DSB repair, PAR is recognized by several repair machineries, such as the BRCA1-BARD1 complex, the MRN complex and the hSSB1-INTS complex.
Figure 4
Figure 4. The molecular mechanism of the recruitment of BRCA1 to DNA lesions
BRCA1 and BARD1 form heterodimer via the interaction between the Ring domains. Upon DNA damage, PAR quickly recruits the BRCA1-BARD1 complex via the interaction with the BARD1 BRCT. The BRCT of BRCA1 is important for the stable retention of BRCA1/BARD1 complex at the sites of DNA damage through the interaction with Abraxas/CCDC98.
Figure 5
Figure 5. A new model of how PARP inhibitors selectively suppress BRCA1-deficient tumors
Hypomorphic mutations of BRCA1 abolish the BRCA1 BRCT domain. The mutants can still be transiently recruited to the sites of DNA damage by PAR. BRCA1 mutants fail to repair all the lesions, and induce genomic instability and tumorigenesis. Treating these tumor cells with PARP inhibitors abolishes the transient recruitment of mutant BRCA1. Without BRCA1, tumor cells undergo apoptosis. However, a set of cancer-associated mutations exist in the Ring domain of BRCA1 or the BRCT domain of BARD1. In these cases, PAR does not affect the recruitment of BRCA1. Thus, PARP inhibitors do not selectively kill tumor cells with these mutations.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40:179–204. - PMC - PubMed
    1. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–1078. - PMC - PubMed
    1. Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481:287–294. - PubMed
    1. Kim MY, Zhang T, Kraus WL. Poly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal. Genes Dev. 2005;19:1951–1967. - PubMed
    1. Luo X, Kraus WL. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev. 2012;26:417–432. - PMC - PubMed

Publication types

MeSH terms

Substances