LIG3 (DNA Ligase 3)

PARP inhibition with olaparib increased residual γH2AX/53BP1 foci post-irradiation in ERG+ cells, indicating enhanced radiosensitization...These findings suggest that ERG expression promotes dependency on PARP1-EJ, rendering ERG+ PCa more susceptible to PARP inhibition. Combining PARP inhibitors with RT may offer a tumor-selective radiosensitization for ERG+ PCa patients.

Taken together, our findings indicate that Alt-NHEJ inhibitors are potential immune-stimulating agents for MM with hyperactivation of cGAS-STING pathway, coherently with our working hypothesis.

Finally, inhibition of the ATR regulators PRMT1 or PRMT5 synergizes with PARG inhibition, implicating replication-associated BER/SSBR and PARylation in the activation of the PRMT1/PRMT5/ATR axis. This study highlights the role of BER/SSBR in protecting the cell during S-phase to suppress PARylation-induced checkpoint activation, which may suggest a potential intervention strategy for PARG inhibitor-resistant tumors.

Blood samples were collected, and gene polymorphisms were identified using PCR-RFLP technique. Our study results revealed a statistically significant association between gene polymorphisms OGG1-Ser326Cys (p = 0.008), XRCC1-Arg194Trp (p = 0.009), XRCC1-Arg399Gln (p < 0.001), APEX1-Asp148Glu (p < 0.001) and the occurrence of leukoplakia, OSMF and OSCC.

We used known compound UNC2025 as positive control and one million compounds was retrieved from different databases (OTAVA, ZINC, ChEMBL) and docked with MERTK protein...The study finds critical residues which serve a vital part in binding with the inhibitor and the active site of the MERTK protein, i.e., Phe598, Gly599, Lys619, Arg629, Glu633, Glu637, Arg722, Asp723, Arg727, Asp741, Gly743, Leu744, Lys746, Arg758, Ala760, and Lys761 through decomposed binding free energy analysis. This study focuses on the pursuit of several MERTK protein targets, which could have consequences for the development of novel therapeutics for various cancers.

This study revealed a 13-fold increase of eccDNA in HGSOC compared to normal tissues, with significant enrichment in promoter and coding regions. eccDNA-derived miRNAs (eccMIRs) were shown to enhance cancer cell proliferation, invasion, and tumor growth through the expression of oncogenic miRNA sequences. The study highlights the importance of the MMEJ pathway in eccDNA generation and proposes that targeting eccDNA biogenesis in this aggressive malignancy presents a novel therapeutic opportunity.

The predictive potential of AAbs as biomarkers of ICI therapy is promising. Further evaluation in larger cohorts is needed to validate our findings and elucidate the underlying mechanism.

Notably, PARylation-dependent acidic microenvironments mediated by the Lig3-YY1 complex play a critical role in the formation of Z-DNA, which potentially facilitates the fusion-religation process to drive ecDNA biogenesis. Furthermore, our findings establish PARP inhibitors as specific agents for ecDNA-targeted strategies in cancer therapy.

The potential of novobiocin, recently identified to be a DNA POLѲ inhibitor, to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells, tumor-bearing mice and in Phase 1 clinical trial in combination with cyclophosphamide or cisplatin...In simultaneous combination with ART-558, talazoparib produced greater-than-additive cytotoxicity at the highest concentrations of the POLѲ inhibitors in the 922,993-354-T-J3-PDC endometrial serous carcinoma mct-spheroids. Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922,993-354-T-J3 mct-spheroids...Regions of potentiation were evident in the 922,993-354-T-J3-PDC endometrial carcinoma survival surface plots at the highest concentration of paclitaxel tested, while regions of potentiation were evident in the paclitaxel mid-concentrations of the 299,254-011-R-J1-PDC melanoma mct-spheroids survival surface plots as determined by the Bliss independence calculation...POLѲ allosteric inhibitors, novobiocin, ART558 and RP-6685, have entered clinical trial. The current study explores the cytotoxicity of POLѲ inhibitors in combination with anticancer drugs and investigational agents in patient-derived cell lines grown as mct-spheroids.

This study emphasizes the mutation-specific effects of LIG3 nsSNPs on protein stability and ligand interactions. We recommend identifying DM-BFC to advance personalized medicine approaches for targeting deleterious variants, following in-vitro and in-vivo validation for AML treatment.

Recently, these proteins have been implicated in a back-up pathway for joining Okazaki fragments that appears to have a critical function even in cells with no defect in the major LigI-dependent pathway. Finally, we discuss the effects of FDA-approved PARP1/2 inhibitors on DNA replication and repair in cancer and non-malignant cells and the potential utility of DNA ligase inhibitors as cancer therapeutics.

Correspondingly, ecDNA maintenance requires DDR, and inhibiting DDR impairs the circularization of ecDNA. In summary, we demonstrate reciprocal interactions between ecDNA maintenance and DDR, providing new insights into the detection and treatment of ecDNA+ tumors.