IndraLab

"Additionally, USP28 promoted olaparib resistance by stabilizing SOX9 protein and enhancing DNA damage repair."

"Monomeric USP28 induces replication-dependent DNA damage."

"Western blot analysis of γH2AX came to the same conclusions, showing that inhibition of USP28 induces DNA damage (Fig. 7F, I), while overexpression of USP28 led to an alleviated DNA damage upon olaparib treatment (Fig. 7G)."

"Arrest of cell cycle by serum deprivation also decreased and equalized γH2AX levels in both cell lines (Supplementary Figure S3C), suggesting that DNA damage induced by monomeric USP28 requires DNA replication.Assessment of DNA breakage using neutral comet assay (60) showed an increased level of DSBs in cells expressing USP28-M compared to USP28-WT (Figure 3D)."

"In previous experiments, we found that targeting USP28 with AZ1 induces DNA damage in non-small cell lung cancer while also inhibiting DNA repair."

"Abrogation of USP28 induces DNA damage and cell death."

"Summarizing the research findings above, we can link USP28 inhibition and AZ1-induced events such as cell cycle alterations, apoptosis, immune activation, and DNA damage: Targeting USP28 induces DNA damage, activating Noxa-mediated mitochondrial apoptosis; DNA damage and mitochondrial apoptosis release dsDNA and mtDNA which activate tumor cell immunogenicity via the cGAS-STING signaling pathway; simultaneously targeting USP28 leads to c-MYC degradation, causing cell cycle arrest and inhibition of DNA repair, further promoting DNA damage-induced cell apoptosis mediated by Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA.Platinum-based drugs are commonly used DNA-damaging agents widely employed in the treatment of malignant tumors."