RESUMEN
DNA damage plays a significant role in the tumorigenesis and progression of the disease. Abnormal DNA repair affects the therapy and prognosis of cancer. In this study, it is demonstrated that the deubiquitinase USP25 promotes non-homologous end joining (NHEJ), which in turn contributes to chemoresistance in cancer. It is shown that USP25 deubiquitinates SHLD2 at the K64 site, which enhances its binding with REV7 and promotes NHEJ. Furthermore, USP25 deficiency impairs NHEJ-mediated DNA repair and reduces class switch recombination (CSR) in USP25-deficient mice. USP25 is overexpressed in a subset of colon cancers. Depletion of USP25 sensitizes colon cancer cells to IR, 5-Fu, and cisplatin. TRIM25 is also identified, an E3 ligase, as the enzyme responsible for degrading USP25. Downregulation of TRIM25 leads to an increase in USP25 levels, which in turn induces chemoresistance in colon cancer cells. Finally, a peptide that disrupts the USP25-SHLD2 interaction is successfully identified, impairing NHEJ and increasing sensitivity to chemotherapy in PDX model. Overall, these findings reveal USP25 as a critical effector of SHLD2 in regulating the NHEJ repair pathway and suggest its potential as a therapeutic target for cancer therapy.
RESUMEN
Purpose: Mobile phone addiction has motivated a widespread concern in recent years. From a developmental perspective, this study explored the predictive relations between life events, boredom proneness (BP), and mobile phone addiction tendency (MPAT) among undergraduate students. It also tested the longitudinal mediation of BP between life events and MPAT. Methods: Five hundred and eighty-four undergraduate students completed the Mobile Phone Addiction Tendency Scale, the Adolescent Self-Rating Life Events Checklist, and the Boredom Proneness Scale-Short Form. A longitudinal mediation analysis based on latent growth modeling was conducted to test the hypothesized relationships among life events, BP and MPAT. Results: Latent growth modeling (LGM) showed that the BP and MPAT of undergraduate students both increased linearly. A longitudinal model based on LGM showed that negative life events both directly and indirectly affected the initial level and the growth rate of the MPAT through the mediating effect of the initial level of BP. Conclusion: These results reveal that negative life events are an indicator of the development of MPAT. It has practical implications for calling for adopting health coping styles when facing negative life events. Supported for reducing college students' boredom proneness in order to lessen the tendency towards mobile phone addiction to improve their mental health.
RESUMEN
DNA damage response is a key signal transduction pathway in triggering ageing and tumor progression. Abnormal alternative splicing (AS) is associated with tumors and ageing. However, the role of AS factors associated with DNA damage repair and ageing in stomach adenocarcinoma (STAD) remains unclear. We downloaded the percentage of splicing (PSI) values for AS in STAD from the TCGA SpliceSeq database. The PSI values of DNA repair gene AS events were integrated with STAD patient survival data for Cox regression analysis. The prediction model for the overall survival (OS) was constructed by the clinical traits. The tumor immune microenvironment was analyzed by CIBERSORT and ESTIMATE. We detected 824 AS events originating from 166 DNA repair genes. Cox regression analysis provided 21 prognostic AS events connected with OS statistically, and a prognostic prediction model was constructed. The expression of these AS factors was higher in STAD tumors. DDB2 high senescence levels were associated with active immune responses and better survival in STAD patients. We built a novel prognostic model founded on DNA repair genes with AS events and identified that DDB2 may be a potential biomarker to apply in clinics.
