通过广泛的组合泛癌CRISPR筛选确定的合成致死基因对纲要

IF 10.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Victoria Harle, Victoria Offord, Birkan Gökbağ, Lazaros Fotopoulos, Thomas Williams, Diana Alexander, Ishan Mehta, Nicola A. Thompson, Rebeca Olvera-León, Stefan Peidli, Vivek Iyer, Emanuel Gonçalves, Narod Kebabci, Barbara De Kegel, Joris van de Haar, Lang Li, Colm J. Ryan, David J. Adams
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引用次数: 0

摘要

合成致死相互作用是有吸引力的治疗候选者,因为它们能够选择性靶向癌细胞,其中体细胞改变破坏了合成致死基因对的一个成员,而不影响正常组织,从而最大限度地减少脱靶毒性。尽管有这种潜力,但已确定和验证的合成致死基因对的数量有限。我们建立了一个双导CRISPR/Cas9文库,并分析了来自黑色素瘤、胰腺癌和肺癌谱系的27种癌细胞系的472对预测合成致死对。我们报告了117种癌症类型内部和之间的基因相互作用的强大集合,并探索了它们作为治疗靶点的候选性。我们发现SLC25A28是一个有吸引力的靶标,因为它的合成致死平行伴侣SLC25A37是纯合缺失的泛癌。我们产生了Slc25a28基因敲除小鼠,结果表明,除了一些小鼠患有白内障外,这些小鼠是正常的;这表明SLC25A28的抑制不太可能与严重的毒性有关。我们提供并验证了跨癌症类型的合成致死相互作用的广泛集合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A compendium of synthetic lethal gene pairs defined by extensive combinatorial pan-cancer CRISPR screening
Synthetic lethal interactions are attractive therapeutic candidates as they enable selective targeting of cancer cells in which somatic alterations have disrupted one member of a synthetic lethal gene pair while leaving normal tissues untouched, thus minimising off-target toxicity. Despite this potential, the number of well-established and validated synthetic lethal gene pairs is modest. We generate a dual-guide CRISPR/Cas9 Library and analyse 472 predicted synthetic lethal pairs in 27 cancer cell Lines from melanoma, pancreatic and lung cancer Lineages. We report a robust collection of 117 genetic interactions within and across cancer types and explore their candidacy as therapeutic targets. We show that SLC25A28 is an attractive target since its synthetic lethal paralog partner SLC25A37 is homozygously deleted pan-cancer. We generate knockout mice for Slc25a28 revealing that, except for cataracts in some mice, these animals are normal; suggesting inhibition of SLC25A28 is unlikely to be associated with profound toxicity. We provide and validate an extensive collection of synthetic lethal interactions across cancer types.
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来源期刊
Genome Biology
Genome Biology Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
21.00
自引率
3.30%
发文量
241
审稿时长
2 months
期刊介绍: Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens. With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category. Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.
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