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Beyond DNA Repair: Additional Functions of PARP-1 in Cancer
1Department of Radiation Oncology, School of Medicine, The University of Alabama at Birmingham , Birmingham, AL , USA.
Abstract:
Poly(ADP-ribose) polymerases (PARPs) are DNA-dependent nuclear enzymes that transfer negatively charged ADP-ribose moieties from cellular nicotinamide-adenine-dinucleotide (NAD(+)) to a variety of protein substrates, altering protein-protein and protein-DNA interactions. The most studied of these enzymes is poly(ADP-ribose) polymerase-1 (PARP-1), which is an excellent therapeutic target in cancer due to its pivotal role in the DNA damage response. Clinical studies have shown susceptibility to PARP inhibitors in DNA repair defective cancers with only mild adverse side effects. Interestingly, additional studies are emerging which demonstrate a role for this therapy in DNA repair proficient tumors through a variety of mechanisms. In this review, we will discuss additional functions of PARP-1 - including regulation of inflammatory mediators, cellular energetics and death pathways, gene transcription, sex hormone- and ERK-mediated signaling, and mitosis - and the role these PARP-1-mediated processes play in oncogenesis, cancer progression, and the development of therapeutic resistance. As PARP-1 can act in both a pro- and anti-tumor manner depending on the context, it is important to consider the global effects of this protein in determining when, and how, to best use PARP inhibitors in anticancer therapy.
Insights
Poly(ADP-ribose) polymerases (PARPs) are key enzymes in DNA repair and cancer therapy. Understanding PARP-1
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Poly(ADP-ribose) polymerases (PARPs) are DNA-dependent enzymes regulating cellular processes.
- Poly(ADP-ribose) polymerase-1 (PARP-1) is a crucial target in cancer therapy due to its role in DNA damage response.
- PARP inhibitors show efficacy in DNA repair-deficient cancers with manageable side effects.
Purpose of the Study:
- To review the diverse functions of PARP-1 beyond DNA repair.
- To explore PARP-1's roles in inflammation, energetics, gene transcription, signaling, and mitosis.
- To discuss the implications of these functions in oncogenesis and therapeutic resistance.
Main Methods:
- Literature review of existing studies on PARP-1 functions and therapeutic applications.
- Analysis of PARP-1's involvement in various cellular pathways.
- Synthesis of information regarding PARP-1's dual role in tumor progression.
Main Results:
- PARP-1 regulates inflammatory mediators, cellular energetics, and cell death pathways.
- PARP-1 influences gene transcription, signaling pathways (including ERK), and mitosis.
- PARP-1 exhibits context-dependent pro- and anti-tumor activities.
Conclusions:
- PARP-1 has multifaceted roles in cancer, extending beyond DNA repair.
- Understanding these diverse functions is critical for optimizing PARP inhibitor therapy.
- Context-specific evaluation of PARP-1's global effects is essential for effective cancer treatment strategies.
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