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⇱ Roles of ADP-Ribosyltransferases in Cancer - PubMed

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Abstract

ADP-ribosyltransferases (ARTs) regulate key processes in cancer, including DNA repair, transcription, immune responses, and treatment resistance. The clostridial toxin-like ADP-ribosyltransferase (ARTC) family and the diphtheria toxin-like ADP-ribosyltransferase (ARTD) family play a crucial role in genomic stability by modification of proteins either with mono(ADP-ribosyl)ation (MARylation) or poly(ADP-ribosyl)ation (PARylation). These ARTs are promising therapeutic targets and could serve as biomarkers in cancer management. This review explores the roles of these enzymes and current knowledge on specific inhibitors. A literature search was conducted in PubMed and Google Scholar to identify studies published between 1992 and 2025 on ADP-ribosyltransferases and their roles in cancer. Among ARTC family, ART1 and ART3 modulate the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, influencing angiogenesis, tumor growth, and immune evasion via cluster of differentiation 8+ (CD8+) T-cell apoptosis. Within the ARTD family, poly(ADP-ribose)polymerase (PARP)1 and PARP2 are activated by DNA single-strand breaks and are clinically validated targets in cancers with homologous recombination deficiency, such as breast cancer susceptibility genes 1/2 (BRCA1/2)-mutated breast cancer. Their inhibition exemplifies synthetic lethality and has shown clinical efficacy. Four PARP inhibitors, olaparib, niraparib, rucaparib, are approved by the Food and Drug Administration (FDA) approved. Despite these advances, selective inhibitors for ARTs remain underexplored. Ongoing research focuses on overcoming PARP inhibitor resistance, improving biomarker-driven patient selection, and expanding therapeutic strategies that target ART-related pathways.

Keywords: ADP-ribosyltransferases (ARTs); Cancer therapeutics; gene targets; poly(ADP-ribose)polymerase (PARPs); synthetic lethality.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

👁 Figure 1
Figure 1. An overview of ADP-ribosyltransferase 1 (ART1)-mediated pathways and their roles in tumor biology. Abb: IKK: Inhibitor of Kappa B Kinase Complex; NF-κB: Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells; P2X7R: P2X7 Receptor; CD8+: Cluster of Differentiation 8+; IL-6: Interleukin-6; STAT3: Signal Transducer and Activator of Transcription 3; PI3K: Phosphoinositide-3-Kinase; AKT: Protein Kinase B; HIF-1α: Hypoxia-Inducible Factor 1-Alpha; FOXO: Forkhead Box Transcription Factor; MARylate: Mono-ADP-Ribosylate; GPCR: G Protein-Coupled Receptor.
👁 Figure 2
Figure 2. ADP-ribosyltransferase 1 (ART1) affects the interleukin-6 (IL-6)/glycoprotein 130 (gp130)/signal transducer and activator of transcription 3 (STAT3), producing more IL-6 cytokines through upregulation of gene expression from IL-6 genes and other cell survival and proliferation genes via STAT3 dimers. Abb: JAK: Janus Kinase; STAT1: Signal Transducer and Activator of Transcription 1.
👁 Figure 3
Figure 3. ADP-ribosyltransferase 1 (ART1) regulates the phosphoinositide-3-kinase (PI3K)/Protein Kinase B (AKT) pathway with many downstream effects on transcription factors, which include downregulating forkhead box transcription (FOXO)and its tumor suppression effects, upregulating hypoxia-inducible factor 1-alpha (HIF-1α), promoting angiogenesis through increasing transcription of human fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) genes, and upregulating a modified nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway for increased cell proliferation and reduced apoptosis rates [55,56]. ART3 also affects transcription of genes in cell growth and division through a closely-related mitogen—activated protein kinases (MAPK)/extracellular regulated kinase (ERK) pathway, and via Protein Kinase B (AKT).
👁 Figure 4
Figure 4. Poly(ADP-ribose)polymerase (PARP) family members in DNA repair. Schematic showing the involvement of PARP1, PARP2, PARP3, PARP4 and PARP14 in DNA repair and their associated proteins. PARP1, PARP2, PARP4 are associated with single-strand breaks (SSBs) while PARP3 and PARP14 are associated with double-strand breaks (DSBs). Abb: PARP: Poly(ADP-Ribose)Polymerase; BRCA: Breast Cancer Susceptibility Gene; ATM: Ataxia-Telangiectasia Mutated; ATR: Protein Kinase B; CHK1/2: Checkpoint Kinase 1; XRCC4: X-Ray Repair Cross-Complementing Protein 4.
👁 Figure 5
Figure 5. PARP11-mediated immune evasion mechanism. Diagram illustrating how PARP11 expression in tumor-infiltrating regulatory T (TI-Treg) cells downregulates INFAR1 expression in T cells, thereby promoting immune evasion [32,88]. Abb: PARP11: Poly(ADP-Ribose)Polymerase 11; CD8+: Cluster of Differentiation 8+; IL-10: Interleukin-10; TGF-β: Transforming Growth Factor Beta; PGE2: Prostaglandin E2; TI-Treg: Tumor-Infiltrating-T Regulatory Cell.
👁 Figure 6
Figure 6. PARP10, PARP12, and PARP14 all act through the PI3K/ART or related HIF-1α, FOXO, and NF-κB pathways. Abb: PIP2: Phosphatidylinositol Phosphate 2; PIP3: Phosphatidylinositol Phosphate 3; PI3K: Phosphoinositide 3-Kinase; PARP: Poly(ADP-Ribose)Polymerase; PDK1: Phosphoinositide-Dependent Kinase-1; AKT: Protein Kinase B; HIF-1α: Hypoxia-Inducible Factor 1-Alpha; FOXO: Forkhead Box Transcription Factor; NF-κB: Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells.

References

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