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ATM is required for the repair of Topotecan-induced replication-associated double-strand breaks

Sabrina Köcher1, Anja Spies-Naumann, Malte Kriegs

  • 1Heinrich-Pette-Institute Leibniz-Institute for Experimental Virology, Hamburg, Germany; Institute of Radiobiology and Molecular Radiation Oncology, Philipps-University of Marburg, Germany.

Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology
|August 10, 2013
PubMed
Abstract

Insights

The Ataxia-Telangiectasia Mutated (ATM) kinase is crucial for repairing DNA double-strand breaks (DSBs) that occur during replication. This study shows ATM is essential for homology-directed repair of Topotecan-induced DSBs at replication forks.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • DNA replication is a critical process and a target for anti-cancer drugs.
  • Understanding DNA repair mechanisms, especially those associated with replication, is vital for developing effective therapies.
  • The role of Ataxia-Telangiectasia Mutated (ATM) kinase in repairing replication-associated DNA double-strand breaks (DSBs) remains unclear.

Purpose of the Study:

  • To investigate the involvement of ATM in the homology-directed repair (HDR) of DSBs that arise indirectly during DNA replication.
  • To determine if ATM plays a role in repairing replication-associated DSBs induced by Topotecan (TPT).

Main Methods:

  • Experiments utilized ATM-deficient and ATM-proficient human cells.
  • Replication-associated DSBs were induced using Topotecan (TPT) and compared to γ-irradiation (IR).
  • Assessed cell survival, DSB repair (γH2AX/53BP1 foci), HDR (Rad51 foci), cell cycle distribution, and protein expression.

Main Results:

  • ATM-deficiency resulted in increased residual DSBs, S/G2 cell cycle arrest, and reduced survival after TPT treatment.
  • Persistent Rad51 foci were observed after TPT treatment, similar to IR, indicating HDR involvement.
  • ATM plays a significant role in the repair of TPT-induced DSBs during replication.

Conclusions:

  • ATM is essential for the complete homology-directed repair of Topotecan-induced DSBs that occur indirectly at replication forks.
  • These findings highlight ATM's critical role in maintaining genomic stability during DNA replication under genotoxic stress.
Keywords:
ATMHomology-directed repairReplication-associated DSBsSKXTopotecan

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