POLG2 (DNA Polymerase Gamma 2, Accessory Subunit)

Pharmacodynamic findings confirm that POLB 001 inhibits LPS-induced local and systemic inflammation in vivo through inhibition of p38 MAPK. https://onderzoekmetmensen.nl/en/trial/51741, identifier NL81214.056.22.

In this review, we have provided a potential example to illustrate the mechanistic insight how PARP1 inhibitor (Olaparib) induces replication associated double strand breaks in POLB deficient cells and DNA mediated innate immune signal activation that likely enhances immune based therapy. Based on our previously published data and the current recent findings, POLB status of the patient likely provide genetic indicators to stratify gastric cancer patient. Overall, in this review article, we presented a new direction to highlight the opportunity to exploit POLB genetic defect in cancer cells to enhance treatment response and to explore synergistic effect to target gastric cancer cells that harbor aberrant DNA polymerase beta function with immune based therapeutic strategy.

Integration of genomic profiling with genetic mapping found an insertion-deletion variant that explains ancestry-associated differences in 1,25D regulation of POLB, an oxidative DNA repair enzyme involved in colorectal carcinogenesis, which also showed signals of positive natural selection. These findings highlight the importance of including diverse individuals in functional genomics studies to identify potential drivers of population-level differences relevant for clinical outcomes, and to uncover functional mechanisms that may be obscured by ancestry variation.

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.

Importantly, the expression trends of FASN, VDAC2, and RHOT2 in the BLCA and control groups within the TCGA-BLCA and GSE13507 datasets, as well as in clinical samples, were consistent and significant. In this study, a novel prognostic model for bladder cancer was constructed based on POLB, FASN, CASP9, VDAC2, and RHOT2, which provided preliminary references for the prognostic evaluation of bladder cancer and subsequent studies related to its diagnosis and treatment.

Analysis on drug sensitivity revealed that the high-risk group was highly sensitive to rapamycin. Additionally, it was verified that IFFO1, ANKRD10 and POLG2 were markedly upregulated and CHMP4A was also markedly downregulated in A375 cells by RT-PCR, which was consistent with the partial results of biological analysis. Overall, it would provide valuable information about the GRGs of prognosis and immune status in melanoma.

Our systematic bioinformatics approach identifies new DNA repair genes and mutagens that exhibit differential activity during the S phase. These findings pave the way for further investigation of factors that contribute to genome instability during cancer transformation.

Importantly, tumours in an in vivo xenograft model were sensitive to combined Nrf2 and ALDH2 inhibition. Given the role of the Nrf2-ALDH2/PolG2 pathway in the progression of AML, inhibition of this pathway may prevent disease relapse/resistance and promote sensitisation to chemotherapy.

Crucially, Milatuzumab, a CD74-targeting antibody, reversed MIF-induced TAM immunosuppression in vitro. Our research provides a comprehensive map of GC-TAM heterogeneity; reveals that the MIF-CD74 axis is a key driver of TAM-mediated immune suppression; and proposes that CD74 blockade is a new therapeutic strategy for GC.

The EC prediction model based on these four genes demonstrated high performance (AUC = 0.974 for the training set; AUC = 0.966 for the validation set), and these genes were significantly associated with immune cell infiltration (P < 0.05). CDKN2A, DDA1, LRRC42, and POLB may be common causative genes for OA and early-stage EC, potentially serving as targets for drug intervention.

The translational nature of this interaction was further examined using murine xenograft models of BRCA1 mutant and BRCA2 null cell lines, wherein the combination of POLB knockout and niraparib led to profound tumor regression and prevented tumor regrowth even after cessation of treatment. Together, these results suggest that POLB is a synergistic enhancer of the synthetic lethal interaction between PARP and BRCA and support POLB as a promising therapeutic target for improving antitumor responses to PARPi in HR-deficient cancers.

In addition, this study revealed expressional alterations of neurotoxicity marker (ache), DNA repair (ogg1, apex1, creb1, polb, mlh1, msh2 and msh6) and tumor suppressor (p53, brca2) genes. Results of ROS generation, MDA level, histopathological analysis, gene expression and immunofluorescence study confirmed that As and Cr did not show antagonistic effects in combination rather indicated additive effects which was dose-dependent but not always linear.