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DNA end resection by CtIP and exonuclease 1 prevents genomic instability

Wassim Eid, Martin Steger, Mahmoud El‐Shemerly, Lorenza P Ferretti, Javier Peña‐Diaz, Christiane König, Emanuele Valtorta, Alessandro A Sartori, Stefano Ferrari

Author Affiliations

  1. Wassim Eid1,
  2. Martin Steger1,
  3. Mahmoud El‐Shemerly1,
  4. Lorenza P Ferretti1,
  5. Javier Peña‐Diaz1,
  6. Christiane König1,
  7. Emanuele Valtorta1,
  8. Alessandro A Sartori (sartori{at}imcr.uzh.ch)*,1 and
  9. Stefano Ferrari (sferrari{at}imcr.uzh.ch)*,1
  1. 1 Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, Irchel Campus, Zurich, CH‐8057, Switzerland
  1. * Tel: +41 44 635 3473; Fax: +41 44 635 3484; E‐mail: sartori{at}imcr.uzh.ch

    Tel: +41 44 635 3471; Fax: +41 44 635 3484; E‐mail: sferrari{at}imcr.uzh.ch

Abstract

End resection of DNA—which is essential for the repair of DNA double‐strand breaks (DSBs) by homologous recombination—relies first on the partnership between MRE11–RAD50–NBS1 (MRN) and CtIP, followed by a processive step involving helicases and exonucleases such as exonuclease 1 (EXO1). In this study, we show that the localization of EXO1 to DSBs depends on both CtIP and MRN. We also establish that CtIP interacts with EXO1 and restrains its exonucleolytic activity in vitro. Finally, we show that on exposure to camptothecin, depletion of EXO1 in CtIP‐deficient cells increases the frequency of DNA–PK‐dependent radial chromosome formation. Thus, our study identifies new functions of CtIP and EXO1 in DNA end resection and provides new information on the regulation of DSB repair pathways, which is a key factor in the maintenance of genome integrity.

  • Received May 26, 2010.
  • Revision received September 2, 2010.
  • Accepted September 13, 2010.