Ask about this productRelated genes to: PARP12 antibody
- Gene:
- PARP12 NIH gene
- Name:
- poly(ADP-ribose) polymerase family member 12
- Previous symbol:
- ZC3HDC1
- Synonyms:
- FLJ22693, PARP-12, ZC3H1
- Chromosome:
- 7q34
- Locus Type:
- gene with protein product
- Date approved:
- 2003-12-10
- Date modifiied:
- 2015-11-06
Related products to: PARP12 antibody
Related articles to: PARP12 antibody
- PARP1/2 inhibitors have received FDA approval for pancreatic cancer harboring BRCA1/2 mutations and homologous recombination (HR) deficiency; however, their limited indications restrict their broader clinical application. Previous studies have demonstrated that PARP7, a member of the PARP family, enhances tumor sensitivity to PARP1/2 inhibition. However, the mechanisms underlying their synergistic effects in pancreatic cancer remain unclear. Herein, we found that combined inhibition of PARP1/2 and PARP7 using Olaparib and XYL-1 significantly inhibited the proliferation of SW1990 and CFPAC cells compared with either single agent. Furthermore, XYL-1 and Olaparib cooperatively caused DNA damage and induced cell apoptosis in SW1990 cells. Consistently, combined treatment with XYL-1 and Olaparib significantly suppressed SW1990 tumor growth compared with single-agent treatment in mouse xenograft models, accompanied by elevated levels of phosphorylated H2AX in tumor tissues. Notably, bioinformatic analyses and mechanistic studies identified SCD1 and BRCA1 as key mediators of the synergistic antitumor effects of XYL-1 and Olaparib. More importantly, the combination of XYL-1 and Olaparib synergistically downregulated the expression of SCD1 and BRCA1, thereby impairing the HR-mediated DNA repair pathway. Collectively, these findings suggest that dual targeting of PARP7 and PARP1/2 may represent a promising therapeutic strategy for BRCA-proficient pancreatic cancer. - Source: PubMed
Publication date: 2026/08/10
Yang YeHuang LeiDu YaruZhu QingyueDai LiQian Bingjun - Neuroinflammation is a key mechanism underlying neuropathic pain, in which microglial cells play a central role. Poly(ADP-ribose) polymerase 12 (PARP12) is an interferon-stimulated gene (ISG) containing a predicted RNA-binding domain and may be involved in inflammatory regulation and RNA metabolism; however, its posttranscriptional regulatory functions in microglia remain to be fully elucidated. PARP12 was stably knocked down in BV2 microglial cells using lentiviral shRNA. Quantitative PCR confirmed a significant reduction in mRNA levels (knockdown efficiency 78.3%), but Western blot analysis showed no successful downregulation of PARP12 protein levels. Transcriptomic and alternative splicing changes were systematically analyzed using RNA sequencing (RNA-seq), and selected key genes were validated by RT-qPCR. Functional enrichment analysis was performed on differentially expressed genes (DEGs) and regulated alternative splicing events (RASEs). Expression changes of homeostatic microglial markers and classical polarization markers were analyzed from the existing RNA-seq data. Comparisons were made with public proinflammatory microglial signature gene sets. PARP12 mRNA knockdown led to substantial transcriptomic remodeling: 276 DEGs (107 upregulated and 169 downregulated) and 287 significant RASEs were identified. Downregulated DEGs were significantly enriched in inflammatory pathways such as NF-κB, TNF, and chemokine signaling; most core immune genes (including Ccl2, Ptgs2, and C3) showed coordinated downregulation, whereas a smaller subset (Ccl5, Cd81, and S1pr1) was upregulated. Homeostatic microglial markers (Tmem119, P2ry12, Cx3cr1, Sall1, etc.) did not differ significantly between shPARP12 and shNC cells. Splicing analysis revealed altered splicing of immune/metabolism-related genes such as Fyb, Tnfaip8, Lrch4, and Pkm, but changes in protein isoform ratios were not validated. The overall proinflammatory signature gene set was downregulated after PARP12 knockdown. PARP12 mRNA knockdown is closely associated with attenuation of the proinflammatory transcriptional program and widespread alternative splicing changes in BV2 microglial cells. However, given the unsuccessful knockdown at the protein level, the observed changes cannot be directly attributed to loss of PARP12 protein function. Further mechanistic studies combining CRISPR/Cas9 gene knockout and in vivo pathological models are warranted. - Source: PubMed
Publication date: 2026/08/15
Hu BangZhou WenLiChen HuaLi Feng - Developing highly selective PARP1 inhibitors is a promising strategy to improve the therapeutic window compared with dual PARP1/2 inhibitors. Through structure-guided design and optimization, we developed (R)-A17, a novel, highly selective PARP1 inhibitor featuring a unique tricyclic scaffold. It demonstrates nanomolar enzymatic potency (PARP1 IC50 = 2.4 nM), exceptional 65.8-fold selectivity over PARP2, and robust antiproliferative activity in BRCA-deficient cells. (R)-A17 exhibits favorable pharmacokinetic properties with complete oral bioavailability (F = 100%) in mice. Mechanistically, it selectively inhibits PARP1-mediated PARylation and induces DNA damage and G2/M phase arrest. In vivo, oral administration of (R)-A17 produced dose-dependent antitumor efficacy in BRCA mutant xenograft models, achieving tumor growth inhibition values of 57.8, 86.3, and 91.3% at doses of 0.3, 1, and 3 mg/kg, respectively, while also synergizing effectively with liposomal irinotecan in an HCT116 xenograft model. These results establish (R)-A17 as a promising candidate and validate the design strategy for the next-generation PARP1-targeted therapy. - Source: PubMed
Guo ZhongningSun RongrongYang LinyuZou YurongGuo TaoMa ZiyanLiu ShuaiWang PengYuan YongtingYe LingpingChen YonglinQin SonghuiLi NaBai PengYuan QuanYan WeiBo WeichenWang TaijinHu JiankunChen Lijuan - Since the identification of PARP1/2 as synthetic lethal targets in BRCA-deficient breast cancer and the subsequent approval of catalytic domain-targeting PARP inhibitors, the landscape of PARP inhibitors has expanded to encompass a broader chemical tool kit. Beyond PARP1/2's canonical role in DNA repair, PARP inhibitors have revealed context-dependent PARP functions in anticancer immunity, viral infection, neurodegeneration, and cellular organization. These discoveries have motivated new strategies that extend past targeting catalytic domains. In this review, we highlight three emerging directions: () biological insights revealed by PARP1/2 inhibitors in oncology and other settings, () progress in developing inhibitors against PARP family members beyond PARP1/2, and () approaches that target noncatalytic domains or modulate PARP function through mechanisms such as interface disruption and targeted degradation. We conclude by outlining key next steps for advancing PARP pharmacology, including substrate mapping, utilizing rational polypharmacology, targeting ADP-ribose readers and erasers, and expanding structural coverage of PARP family proteins. - Source: PubMed
Publication date: 2026/08/10
Owens Michael CLeung Anthony K L - Talazoparib (TZ) is a potent poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that uniquely traps PARP complexes at sites of single-strand DNA damage thereby offering opportunities for targeted radioligand therapy. Radiolabeled halogenated TZ derivatives were synthesized using boronic ester precursors to enable incorporation of diagnostic and therapeutic radionuclides: 18F for PET imaging, 77Br for Auger electron radiotherapy, and 211At for targeted alpha radiotherapy. Copper-mediated radio-halogenation afforded racemic 18F-TZ, 77Br-TZ, and 211At-TZ in sufficient radiochemical yields (4.3 ± 2.6%, n = 33; 29.0 ± 12.0%, n = 4; 3.6 ± 3.8%, n = 9, respectively), ∼99% radiochemical purity and proven stability under formulation conditions. Molecular dynamics simulations of halo-TZ derivatives predicted an inverse relationship between halogen size and PARP1 binding affinity. Indeed, cell uptake of radio-halogenated TZ analogues indicated selective uptake in a panel of cell types that correlated with PARP1 levels but was inversely related to the atomic radii of the halogen series. Despite modest specific activity and specific uptake, 77Br-TZ showed significant cytotoxicity. Further investigation of 18F-TZ with 77Br-TZ as a radiotheranostic pair will be facilitated by the synthetic schemes herein. - Source: PubMed
Muzzioli RiccardoPisaneschi FedericaGammon Seth TSutton Margie NNapoli AriannaPuglielli Raffaele BelliniMcIntosh LaurenTereshatov EvgenyTabacaru GabrielSchultz StevenMcCann LauraBurns Jonathan DYennello SherryPiwnica-Worms David