Discovery of synthetic lethal and tumor suppressor paralog pairs in the human genome.

Autor:	Parrish PCR; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Thomas JD; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Gabel AM; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA., Kamlapurkar S; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Bradley RK; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Berger AH; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: ahberger@fredhutch.org.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Aug 31; Vol. 36 (9), pp. 109597.
DOI:	10.1016/j.celrep.2021.109597
Abstrakt:	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. We apply pgPEN to two cell types and discover that 12% of human paralogs 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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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