期刊
CELL REPORTS
卷 36, 期 9, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109597
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资金
- Lung Cancer Research Foundation
- NSF [DGE-1762114]
- NIH [T32-HG000035]
- NIH/NCI [R01 CA251138, R00 CA197762, R37 CA252050]
- Prevent Cancer Foundation
- Stephen H. Petersdorf Lung Cancer Research Award
- Seattle Translational Tumor Research program
- Innovators Network Endowed Chair
- NIH/NIDDK [R01 DK103854]
- NIH/NHLBI [R01 HL128239, R01 HL151651]
- Edward P. Evans Foundation
- Blood Cancer Discoveries Grant program through the Leukemia & Lymphoma Society
- Department of Defense Breast Cancer Research Program [W81XWH-20-1-0596]
- McIlwain Family Endowed Chair in Data Science
- Leukemia & Lymphoma Society [1344-18]
- NIH/NCI Cancer Center Support Grant [P30 CA015704]
- FHCRC's Scientific Computing Infrastructure [ORIP S10 OD028685]
- Mark Foundation For Cancer Research
- Paul G. Allen Frontiers Group [8023-20]
The use of pgPEN method has led to the discovery of important cancer vulnerabilities and synthetic lethal paralog pairs, which can potentially guide the selection of drug targets and provide insights into genetic interactions in cancer.
CRISPR screens have accelerated the discovery of important cancer vulnerabilities. However, single-gene knockout phenotypes can be masked by redundancy among related genes. Paralogs constitute two-thirds of the human protein-coding genome, so existing methods are likely inadequate for assaying a large portion of gene function. Here, we develop paired guide RNAs for paralog genetic interaction mapping (pgPEN), a pooled CRISPR-Cas9 single- and double-knockout approach targeting more than 2,000 human paralogs. WeapplypgPENto two cell types and discover that12% ofhumanparalogs exhibit synthetic lethality in at least one context. We recover known synthetic lethal paralogs MEK1/MEK2, important drug targets CDK4/CDK6, and other synthetic lethal pairs including CCNL1/CCNL2. Additionally, we identify ten tumor suppressor paralog pairs whose compound loss promotes cell proliferation. These findings nominate drug targets and suggest that paralog genetic interactions could shape the landscape of positive and negative selection in cancer.
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