Journal
CELL
Volume 150, Issue 4, Pages 842-854Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.07.023
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Funding
- NIH/NCI [RC2 CA148268, U54 CA143798, K08 CA122833, T32 GM008313, RO1 GM051923-17, U54 CA112962]
- H.L. Snyder Medical Foundation
- V Foundation
- Conquer Cancer Foundation Young Investigator Award
- Sass Foundation Fellowship
- Marie D. & Pierre Casimir-Lambert Fund
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Due to genome instability, most cancers exhibit loss of regions containing tumor suppressor genes and collateral loss of other genes. To identify cancer-specific vulnerabilities that are the result of copy number losses, we performed integrated analyses of genome-wide copy number and RNAi profiles and identified 56 genes for which gene suppression specifically inhibited the proliferation of cells harboring partial copy number loss of that gene. These CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes are enriched for spliceosome, proteasome, and ribosome components. One CYCLOPS gene, PSMC2, encodes an essential member of the 19S proteasome. Normal cells express excess PSMC2, which resides in a complex with PSMC1, PSMD2, and PSMD5 and acts as a reservoir protecting cells from PSMC2 suppression. Cells harboring partial PSMC2 copy number loss lack this complex and die after PSMC2 suppression. These observations define a distinct class of cancer-specific liabilities resulting from genome instability.
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