Functional deficiency of DNA repair gene EXO5 results in androgen-induced genomic instability and prostate tumorigenesis
| Autor: | Xiaochun Yu, Li Zheng, Jeremy M. Stark, Yilan Zhang, Shafat Ali, Binghui Shen, Hongzhi Li, Weiwei Jin, Jeffrey N. Weitzel, Mian Zhou |
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| Rok vydání: | 2019 |
| Předmět: |
Exonucleases
Male 0301 basic medicine Genome instability Cancer Research Neoplasms Hormone-Dependent DNA Repair Oncogene Proteins Fusion Carcinogenesis DNA repair Biology medicine.disease_cause Genomic Instability Article 03 medical and health sciences 0302 clinical medicine Germline mutation Biomarkers Tumor Genetics medicine Humans DNA Breaks Double-Stranded Genetic Predisposition to Disease Molecular Biology Gene Mutation Prostatic Neoplasms Prognosis Gene Expression Regulation Neoplastic 030104 developmental biology Fusion transcript Case-Control Studies 030220 oncology & carcinogenesis Androgens Homologous recombination Follow-Up Studies |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Germline mutations of DNA double-strand break (DSB) response and repair genes that drive tumorigenesis could be a major cause of prostate cancer (PCa) heritability. In this study, we demonstrated the role of novel exonuclease 5 (EXO5) gene in androgen-induced double strand breaks repair via homology-directed repair pathway and prostate tumorigenesis. Using whole-exome sequencing of samples from 20 PCa families, with three or more siblings diagnosed with metastatic PCa, we identified mutations in 31 genes involved in DSB response and repair. Among them, the L151P mutation in the exonuclease 5 (EXO5) gene was present in all affected siblings in three PCa families. We found two other EXO5 SNPs significantly associated with risk of PCa in cases-controls study from databases of genotype and phenotype (dbGaP), which are in linkage disequilibrium (D' = 1) with Exo5 L151P found in PCa family. The L151 residue is conserved across diverse species and its mutation is deleterious for protein functions, as demonstrated by our bioinformatics analyses. The L151P mutation impairs the DNA repair function of EXO5 due to loss of nuclease activity, as well as failure of nuclear localization. CRISPR elimination of EXO5 in a PCa cell line impaired homology-directed recombination repair (HDR) and caused androgen-induced genomic instability, as indicated by frequent occurrence of the oncogenic fusion transcript TMPRSS2-ERG. Genetic and functional validation of the EXO5 mutations indicated that EXO5 is a risk gene for prostate tumorigenesis, likely due to its functions in HDR. |
| Databáze: | OpenAIRE |
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