The TIP60-ATM axis regulates replication fork stability in BRCA-deficient cells

Emily M. Schleicher, Ashna Dhoonmoon, Lindsey M. Jackson, Jude B. Khatib, Claudia M. Nicolae, George Lucian Moldovan

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Maintenance of replication fork stability is essential for genome preservation. Stalled replication forks can be reversed by translocases such as SMARCAL1, and unless protected through the activity of the BRCA pathway, are subsequently subjected to nucleolytic degradation. The ATM and ATR kinases are master regulators of the DNA damage response. ATM activation upon DNA damage is mediated by the acetyltransferase TIP60. Here, we show that the TIP60-ATM pathway promotes replication fork reversal by recruiting SMARCAL1 to stalled forks. This enables fork degradation in BRCA-deficient cells. We also show that this ATM activity is not shared by ATR. Moreover, we performed a series of genome-wide CRISPR knockout genetic screens to identify genetic determinants of the cellular sensitivity to ATM inhibition in wildtype and BRCA2-knockout cells, and validated the top hits from multiple screens. We provide a valuable list of common genes which regulate the response to multiple ATM inhibitors. Importantly, we identify a differential response of wildtype and BRCA2-deficient cells to these inhibitors. In BRCA2-knockout cells, DNA repair genes (including RAD17, MDC1, and USP28) were essential for survival upon ATM inhibitor treatment, which was not the case in wild-type cells. These findings may eventually help guide the way for rational deployment of ATM inhibitors in the clinic.

Original languageEnglish (US)
Article number33
JournalOncogenesis
Volume11
Issue number1
DOIs
StatePublished - Dec 2022

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'The TIP60-ATM axis regulates replication fork stability in BRCA-deficient cells'. Together they form a unique fingerprint.

Cite this