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Combinatorial CRISPR screen identifies fitness effects of gene paralogues.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Thompson, Nicola A 
Ranzani, Marco 
van der Weyden, Louise  ORCID logo  https://orcid.org/0000-0002-0645-1879
Iyer, Vivek 
Offord, Victoria 

Abstract

Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. Our studies reveal the fitness effects of FAM50A/FAM50B in cancer cells.

Description

Keywords

Animals, Apoptosis, CRISPR-Cas Systems, Cell Line, Tumor, Clustered Regularly Interspaced Short Palindromic Repeats, DNA-Binding Proteins, Gene Knockout Techniques, Genome, Heterografts, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Proteins, RNA-Binding Proteins, Transcriptome

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

12

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (18796)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Wellcome Trust (206388/Z/17/Z)
European Commission Horizon 2020 (H2020) ERC (855741)
Wellcome Trust (203144/A/16/Z)