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Functional deficiency of DNA repair gene EXO5 results in androgen-induced genomic instability and prostate tumorigenesis

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Abstract

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.

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Acknowledgements

We acknowledge Dr. Theodore Krontiris and Dr. Ching Ouyang in City of Hope for providing the genomic DNA samples of prostate cancer families. We thank Charles Warden and Dr. Xiwei Wu for their help in genomic data deposition. Drs. Keely Walker and Kerin K. Higa for proofreading the manuscript. Research reported in this publication included work performed in the Computational Therapeutics and Integrative Genomics core facilities, which are supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572. The work was partially supported by City of Hope institutional Excellence Award to B.H.S.

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The work is supported by City of Hope institutional Excellence Award.

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Authors and Affiliations

  1. Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, USA

    Shafat Ali, Yilan Zhang, Mian Zhou, Weiwei Jin, Li Zheng, Xiaochun Yu, Jeremy M. Stark & Binghui Shen

  2. Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, USA

    Hongzhi Li

  3. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA

    Jeffrey N. Weitzel

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  1. Shafat Ali
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Ali, S., Zhang, Y., Zhou, M. et al. Functional deficiency of DNA repair gene EXO5 results in androgen-induced genomic instability and prostate tumorigenesis. Oncogene 39, 1246–1259 (2020). https://doi.org/10.1038/s41388-019-1061-6

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