Senior scientist Helga B. Landsverk and her co-workers in Randi G. Syljuåsens group have identified new factors in signaling from the transcription machinery to the DNA damage kinase ATR (Ataxia Telangiectasia andRad3-related). The results are published in the prestigious journal Nucleic Acids Research.
Radiotherapy and certain chemotherapeutic drugs kill cancer cells by causing DNA damage. However, DNA damage also induces intracellular signaling cascades, which can contribute to treatment resistance by promoting DNA repair. ATR kinase is a central component of these DNA damage signaling cascades, and clinical trials with ATR-inhibitors are ongoing in several cancer centers.
The new results by Landsverk et al. suggest a novel pathway of ATR activation, which differs from the established view that ATR is activated mainly via single-stranded DNA at sites of stalled replication or processed DNA breaks.
In this novel pathway, ATR is activated by phosphorylation of RNA polymerase II, the main mediator of DNA transcription into mRNA. The phosphatase Pnuts-PP1 suppresses ATR activity by dephosphorylating RNA polymerase II. Furthermore, CDC73, a factor which binds to phosphorylated RNA polymerase II, contributes to stimulating ATR activity.
This work has been performed in collaboration between members of Randi G. Syljuåsens group and Beata Grallert at the Department of Radiation Biology, Institute for Cancer Research (OUH), Laura Trinkle-Mulcahy at the Department of Cellular and Molecular Medicine and Ottawa Institute of Systems Biology, University of Ottawa, Canada and the group of Sérgio F. de Almeida, Institute of Molecular Medicine, University of Lisbon, Portugal.
Regulation of ATR activity via the RNA polymerase II associated factors CDC73 and PNUTS-PP1.
Landsverk HB, Sandquist LE, Sridhara SC, Rødland GE, Sabino JC, de Almeida SF, Grallert B, Trinkle-Mulcahy L, Syljuåsen RG.
Nucleic Acids Res. 2018 Dec 12. doi: 10.1093/nar/gky1233.