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Nucleic Acids Research, 2003, Vol. 31, No. 24 7227-7237
© 2003 Oxford University Press

Article

Repair of a minimal DNA double-strand break by NHEJ requires DNA-PKcs and is controlled by the ATM/ATR checkpoint

Christian Kühne*, Marie-Louise Tjörnhammar, Sándor Pongor, Lawrence Banks and András Simoncsits

International Center for Genetic Engineering and Biotechnology (ICGEB), Area Science Park, Padriciano 99, I-34000 Trieste, Italy

*To whom correspondence should be addressed. Tel: +39 040 375 7371; Fax: +39 040 226 555; Email: kuehne{at}icgeb.org

Mammalian cells primarily rejoin DNA double-strand breaks (DSBs) by the non-homologous end-joining (NHEJ) pathway. The joining of the broken DNA ends appears directly without template and accuracy is ensured by the NHEJ factors that are under ATM/ATR regulated checkpoint control. In the current study we report the engineering of a mono-specific DNA damaging agent. This was used to study the molecular requirements for the repair of the least complex DSB in vivo. Single-chain PvuII restriction enzymes fused to protein delivery sequences transduce cells efficiently and induce blunt end DSBs in vivo. We demonstrate that beside XRCC4/LigaseIV and KU, the DNA-PK catalytic subunit (DNA-PKcs) is also essential for the joining of this low complex DSB in vivo. The appearance of blunt end 3'-hydroxyl and 5'-phosphate DNA DSBs induces a significantly higher frequency of anaphase bridges in cells that do not contain functional DNA-PKcs, suggesting an absolute requirement for DNA-PKcs in the control of chromosomal stability during end joining. Moreover, these minimal blunt end DSBs are sufficient to induce a p53 and ATM/ATR checkpoint function.


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