Aug 23, 2019

VHL Synthetic Lethality Signatures Uncovered by Genotype-Specific CRISPR-Cas9 Screens

The CRISPR Journal
Ning SunNamjin Chung

Abstract

Genome-wide CRISPR-Cas9 essentiality screening represents a powerful approach to identify genetic vulnerabilities in cancer cells. Here, we applied this technology and designed a strategy to identify target genes that are synthetic lethal (SL) with von Hippel-Lindau (VHL) tumor suppressor gene. Inactivation of VHL has been frequently found in clear cell renal cell carcinoma. Its SL partners serve as potential drug targets for the development of targeted cancer therapies. We performed parallel genome-wide CRISPR screens in two pairs of isogenic clear cell renal cell carcinoma cell lines that differ only in the VHL status. Comparative analyses of screening results not only confirmed a well-known role for mTOR signaling in renal carcinoma, but also identified DNA damage response and selenocysteine biosynthesis pathways as novel SL targets in VHL-inactivated cancer cells. Follow-up studies provided cellular and mechanistic insights into SL interactions of these pathway genes with the VHL gene. Our CRISPR and RNA-seq datasets provide a rich resource for future investigation of the function of the VHL tumor suppressor protein. Our work demonstrates the efficiency of CRISPR-based synthetic lethality screening in human isogenic cell pa...Continue Reading

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Mentioned in this Paper

Genome-Wide Association Study
Tumor Suppressor Genes
VHL protein, human
Conventional (Clear Cell) Renal Cell Carcinoma
Isogeneic Graft
Signaling Pathway Gene
Candidate Disease Gene
Response to DNA Damage Stimulus
Parallel Study
Mtor Signaling Pathway BioCarta

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