RT Journal Article
SR Electronic
T1 Tandem duplications lead to loss of fitness effects in CRISPR-Cas9 data
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 325076
DO 10.1101/325076
A1 Emanuel Gonçalves
A1 Fiona M Behan
A1 Sandra Louzada
A1 Damien Arnol
A1 Euan Stronach
A1 Fengtang Yang
A1 Kosuke Yusa
A1 Oliver Stegle
A1 Francesco Iorio
A1 Mathew J Garnett
YR 2018
UL http://biorxiv.org/content/early/2018/05/25/325076.abstract
AB CRISPR-Cas9 gene-editing is widely used to study gene function and is being advanced for therapeutic applications. Structural rearrangements are a ubiquitous feature of cancers and their impact on CRISPR-Cas9 gene-editing has not yet been systematically assessed. Utilising CRISPR-Cas9 knockout screens for 163 cancer cell lines, we demonstrate that targeting tandem amplified regions is highly detrimental to cellular fitness, in contrast to amplifications caused by chromosomal duplications which have little to no effect. Genomically clustered Cas9 double-strand DNA breaks are associated with a strong gene-independent decrease in cell fitness. We systematically identified collateral vulnerabilities in 25% of cancer cells, introduced by tandem amplifications of tissue non-expressed genes. Our analysis demonstrates the importance of structural rearrangements in mediating the effect of CRISPR-Cas9-induced DNA damage, with implications for the use of CRISPR-Cas9 gene-editing technology, and how resulting collateral vulnerabilities are a generalisable strategy to target cancer cells.