POLK (DNA Polymerase Kappa)

Knocking out Ptbp2 in CML cell lines and patient samples decreased Polk levels; when treated with hydroxyurea, these samples exhibited increased DNA damage, evidenced by long comet tails and elevated γH2AX foci, a DNA damage marker; however, re-expressing Polk in Ptbp2-KO cells restored the phenotype...Cells with high levels of Ptbp2 and Polk showed increased sister chromatid exchanges and BrdU incorporation in ex vivo tests, while multinucleated cells with multipolar spindles appeared in in vivo tests. Our results confirm the key role of the Ptbp2-Polk-MRE11 axis in promoting genomic instability and supporting the survival of cells with higher malignancy.

In contrast, Polκ has a non-catalytic role in the extension step of cisplatin ICL repair that is dependent on Rev1 interaction. Our work reveals a key role for Polκ in aldehyde ICL repair and provides mechanistic insights into how different ICL structures determine the choice of TLS polymerases during repair.

These findings underscore the crucial roles of Polɩ and Polκ in conferring TMZ resistance and the potential backup role of homologous recombination in the absence of these TLS polymerases. Targeting these TLS enzymes, along with double-strand break DNA repair inhibition, could, therefore, provide a promising strategy to enhance TMZ's effectiveness in treating GBM.

Interactions with a third magnesium ion and environmental effects on nonbonded interactions, particularly involving key residues, contribute to the kinetic and thermodynamic distinctions between the WT and mutant during the catalytic reaction. The energetics and electronic findings suggest that active site residues favor the catalytic reaction with dCTP3- over dCTP4-.

Collectively, the results suggest that TLS Polκ plays a vital role in the survival, cell death, genotoxicity, and metastatic potential of GBM spheroids in vitro when subjected to TMZ treatment. While the precise mechanisms underpinning this resistance remain elusive, TLS Polκ emerges as a potential therapeutic target for GBM patients.

Signal transduction and cell proliferation were evaluated after treatment with insulin-like growth factor-I (IGF-I) and the selective IGF-I receptor (IGF-IR) inhibitor NVP-ADW742...They lacked tumorigenicity and prominent gene mutations involved in thyroid cancer development, while missense mutations were found in some tumor suppressors as revealed by WGS. The CAT458s and 459 provide a new tool to further clarify the process of thyroid multi-step carcinogenesis and differentiation.

Predictions from bioinformatic tools like SIFT, PolyPhen-2, and FATHMM are based on sequence comparisons and therefore are complementary to POOL but are less capable of predicting biochemical activity. These bioinformatic and computational tools can be used to identify SNP variants with deleterious effects and altered biochemical activity from a large data set.

The in vitro sensitivity of CRC cells to methyl methane sulfonate and cisplatin was determined...Finally, the association of RIP140 expression with better overall survival of CRC patients was observed only when the corresponding tumors exhibited low levels of POLK, thus strengthening the functional link between the two genes in human CRC. The regulation of POLK gene expression by RIP140 could thus contribute to the maintenance of microsatellite stability, and more generally to the control of genome integrity.