1. Academic Validation
  2. DNA-PKcs and ATM epistatically suppress DNA end resection and hyperactivation of ATR-dependent G2-checkpoint in S-phase irradiated cells

DNA-PKcs and ATM epistatically suppress DNA end resection and hyperactivation of ATR-dependent G2-checkpoint in S-phase irradiated cells

  • Sci Rep. 2019 Oct 10;9(1):14597. doi: 10.1038/s41598-019-51071-6.
Emil Mladenov 1 Xiaoxiang Fan 2 Katja Paul-Konietzko 2 Aashish Soni 2 George Iliakis 3
Affiliations

Affiliations

  • 1 Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122, Essen, Germany. [email protected].
  • 2 Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122, Essen, Germany.
  • 3 Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122, Essen, Germany. [email protected].
Abstract

We previously reported that cells exposed to low doses of ionizing radiation (IR) in the G2-phase of the cell cycle activate a checkpoint that is epistatically regulated by ATM and ATR operating as an integrated module. In this module, ATR interphases exclusively with the cell cycle to implement the checkpoint, mainly using Chk1. The ATM/ATR module similarly regulates DNA end-resection at low IR-doses. Strikingly, at high IR-doses, the ATM/ATR coupling relaxes and each kinase exerts independent contributions to resection and the G2-checkpoint. DNA-PKcs links to the ATM/ATR module and defects cause hyper-resection and hyperactivation of G2-checkpoint at all doses examined. Surprisingly, our present report reveals that cells irradiated in S-phase utilize a different form of wiring between DNA-PKcs/ATM/ATR: The checkpoint activated in G2-phase is regulated exclusively by ATR/CHK1; similarly at high and low IR-doses. DNA end-resection supports ATR-activation, but inhibition of ATR leaves resection unchanged. DNA-PKcs and ATM link now epistatically to resection and their inhibition causes hyper-resection and ATR-dependent G2-checkpoint hyperactivation at all IR-doses. We propose that DNA-PKcs, ATM and ATR form a modular unit to regulate DSB processing with their crosstalk distinctly organized in S- and G2- phase, with strong dependence on DSB load only in G2-phase.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-14731
    98.32%, ATM/ATR Inhibitor