Genome-Wide Screening in Human Embryonic Stem Cells Highlights the Hippo Signaling Pathway as Granting Synthetic Viability in ATM Deficiency

Ruth Viner-Breuer, Tamar Golan-Lev, Nissim Benvenisty*, Michal Goldberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

ATM depletion is associated with the multisystemic neurodegenerative syndrome ataxia–telangiectasia (A–T). The exact linkage between neurodegeneration and ATM deficiency has not been established yet, and no treatment is currently available. In this study, we aimed to identify synthetic viable genes in ATM deficiency to highlight potential targets for the treatment of neurodegeneration in A–T. We inhibited ATM kinase activity using the background of a genome-wide haploid pluripotent CRISPR/Cas9 loss-of-function library and examined which mutations confer a growth advantage on ATM-deficient cells specifically. Pathway enrichment analysis of the results revealed the Hippo signaling pathway as a major negative regulator of cellular growth upon ATM inhibition. Indeed, genetic perturbation of the Hippo pathway genes SAV1 and NF2, as well as chemical inhibition of this pathway, specifically promoted the growth of ATM-knockout cells. This effect was demonstrated in both human embryonic stem cells and neural progenitor cells. Therefore, we suggest the Hippo pathway as a candidate target for the treatment of the devastating cerebellar atrophy associated with A–T. In addition to the Hippo pathway, our work points out additional genes, such as the apoptotic regulator BAG6, as synthetic viable with ATM-deficiency. These genes may help to develop drugs for the treatment of A–T patients as well as to define biomarkers for resistance to ATM inhibition-based chemotherapies and to gain new insights into the ATM genetic network.

Original languageAmerican English
Article number1503
JournalCells
Volume12
Issue number11
DOIs
StatePublished - Jun 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Keywords

  • ATM
  • CRISPR loss-of-function library
  • DNA damage
  • Hippo signaling pathway
  • ataxia–telangiectasia
  • human embryonic stem cells
  • neurodegeneration

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