Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

Abstract

BRCA2 mutations are significantly associated with early onset breast cancer, and the tumour suppressing function of BRCA2 has been attributed to its involvement in homologous recombination [1]-mediated DNA repair. In order to identify additional functions of BRCA2, we generated BRCA2-knockout HCT116 human colorectal carcinoma cells. Using genome-wide microarray analyses, we have discovered a link between the loss of BRCA2 and the up-regulation of a subset of interferon (IFN)-related genes, including APOBEC3F and APOBEC3G. The overexpression of IFN-related genes was confirmed in different human BRCA2 −/− and mouse Brca2 −/− tumour cell lines, and was independent of either senescence or apoptosis. In isogenic wild type BRCA2 cells, we observed over-expression of IFN-related genes after treatment with DNAdamaging agents, and following ionizing radiation. Cells with endogenous DNA damage because of defective BRCA1 or RAD51 also exhibited over-expression of IFN-related genes. Transcriptional activity of the IFN-stimulated response element (ISRE) was increased in BRCA2 The GEO number for microarray analysis is GSE54830. Author contributionsHX designed the study, carried out most experiments and wrote the manuscript. JX made the BRCA2 knockout cell lines in HCT116, performed DNA damage repair experiments on BRCA2 knockout cells and wrote part of the manuscript. EV performed the CHIP experiment and was involved in manuscript writing. SJ analyzed the data. JW carried out microarray analysis. RT and VW carried out experiments. TK, CC and SA were involved in study design.

Transition Metal Ions Promote the Bioavailability of Hydrophobic Therapeutics: Cu and Zn Interactions with RNA Polymerase I Inhibitor CX5461

“…[16] Furthermore, the relative values of g k and A k (Cu) are consistent with a2 N,2O coordinatione nvironment. [18] Consistent with previous studies, our data show that cell lines with BRCA2 deficiency are more sensitive to CX5461. To test for such changes in the activity of CX5461,i tw as assayed in the presence and absence of either CuSO 4 or ZnSO 4 against four human cancerc ell lines.…”

Chlorambucil targets BRCA 1/2‐deficient tumours and counteracts PARP inhibitor resistance

“…We next determined chlorambucil anti‐tumour activity using paired BRCA2 +/+ and BRCA2 −/− HCT116 colon carcinoma cell lines, generated in one of our laboratories (Xu et al , ). BRCA2 −/− HCT116 cells showed hypersensitivity to cisplatin and chlorambucil in vitro ().…”

“…Scale bar, 40 µm. lines, generated in one of our laboratories (Xu et al, 2014). BRCA2 À/À HCT116 cells showed hypersensitivity to cisplatin and chlorambucil in vitro (Appendix Fig S6A).…”

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

“…IL-4 decreases DNA damage in murine and human glioblastoma cells when PARP-dependent DNA-repair is required [66]. Over expression of the IFN-related genes are caused by treatment with DNA-damaging agents and following ionizing radiation [67]. Interestingly, this over expression is enhanced in the BRCA2 knockout cells.…”