Is PARP1 a Hero or Villain?

Not counting histones, PARP1 [Poly(ADP-ribose) Polymerase 1] is the most abundant nuclear protein in mammalian cells. While principally known for its role in various types of DNA repair, recent work expanded it’s repertoire to include genome stability maintenance, chromatin remodeling, DNA methylation/gene expression, cellular differentiation, and cell survival modulation via NAD⁺/ATP regulation.¹ It performs Poly(ADP-ribosyl)ation or PARylation by synthesizing long and branched, negatively charged polymers of ADP-ribose (PAR) onto acceptor proteins in a covalent manner at serine, glutamate, and lysine residues. This post-translational modification alters the function and local environment of acceptor proteins in response to cellular stress signaling. Consuming NAD⁺ during PARylation, PARP1 produces over 90% of all PAR for addition to acceptor proteins.²

Involvement in DNA Repair Mechanisms

Aside from yeast, PARP1 is evolutionarily conserved in all eukaryotes. Human PARP1 is a 113 kDa, 1014 amino acid protein. It consists of 3 main functional domains: an N-terminal DNA binding domain with 3 zinc finger DNA binding motifs (ZF1, ZF2, and ZF3) and a nuclear localization signal sandwiched between ZF2 and ZF3, an auto-PARylation domain, and a C-terminal catalytic (ADP-ribosyl) transferase domain.

While ZF1 and ZF2 are required to recognize sites of DNA damage, ZF3 couples this recognition with the protein’s catalytic functions. The auto-PARylation domain consists of a BRCA1 motif and a tryptophan-glycine-arginine (WGR) motif that can move along DNA without activating the catalytic domain. The WGR domain acts in concert with ZF1 and ZF3 to bring areas of DNA damage in proximity to the catalytic domain. Within the catalytic domain, the helical motif restrains NAD⁺ binding until PARP1 binds the DNA damage site. Then, the PARP signature motif presents NAD⁺ for the creation of PAR and the release of nicotinamide.³

After binding to DNA lesions and recruiting repair mechanisms, PARP1 is usually released via auto-PARylation. Cleaved, truncated, or mutated PARP1 produces free 24 kDa N-terminal DNA binding sequences, and this fragment may remain to inhibit DNA repair, augmenting inflammation and apoptosis. However, even excessive induction of full length, intact PARP1 can lead to cell death via exhaustion of available NAD⁺ and subsequent ATP supplies. This process is known as parthanatos. The balance between the induction of repair mechanisms and parthanatos is the focus of current research.⁴

The Two Main Model Systems & Their Opposing Roles

Today, the roles of PARP1 in neurological disease and cancer are still hotly debated. Depending upon the model system employed, it can either be the hero or the villain. Pharmaceutical interventions are known to affect other PARP family members and other proteins that may use NAD⁺. Animal Knock Out strains present total lack of PARP1 from conception forwards. While these animals are healthy and fertile, they are more susceptible to DNA damage and less susceptible to inflammatory inductions. However, in PARP1 and PARP2 KO models, the animals perish in utero. So, there is some salutary effect of PARP2 for survival. In any event, these two main model systems presently generate conflicting assessments. The weight of the evidence currently suggests that, under mild, short-lived stress, PARP1 is a rescuer. But, when stress is high and prolonged, it acts as a terminator.⁵

Currently, the construction of “floxed” PARP1 animals offers selective induction of PARP1 functional loss in a chosen time frame, set against the background of differing stress signaling levels. Hopefully, this method can provide more accurate modeling for relevant disease states.

References

1. Wang, Y. et al. (2021) Therapeutic Potentials of Poly (ADP-Ribose) Polymerase 1 (PARP1) Inhibition in Multiple Sclerosis and Animal Models: Concept Revisiting. Advanced Science, 2102853. Review. https://doi.org/10.1002/advs.202102853.

2. Zong, W. et al. (2022) PARP1: Liaison of Chromatin Remodeling and Transcription. Cancers, 14, 4162. Review. https://doi.org/10.3390/cancers14174162.

3. Kamaletdinova, T. et al. (2019) The Enigmatic Function of PARP1: From PARylation Activity to PAR Readers. Cells, 8, 1625. Review. https://doi.org/10.3390/cells8121625.

4. Wanderley, C.W.S. et al. (2022) Targeting PARP1 to Enhance Anticancer Checkpoint Immunotherapy Response: Rationale and Clinical Implications. Front. Immunol. 13:816642. Review. https://doi.org/10.3389/fimmu.2022.816642.

5. Mao, K and Zhang, G. (2020) The role of PARP1 in neurodegenerative diseases and aging. The FEBS Journal 289. Review. https://doi.org/10.1111/febs.15716.