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Molecular cell v.65 no.4, 2017년, pp.671 - 684.e5   SCI SCIE
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DNA Double-Strand Break Resection Occurs during Non-homologous End Joining in G1 but Is Distinct from Resection during Homologous Recombination

Biehs, Ronja (Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany ) ; Steinlage, Monika (Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany ) ; Barton, Olivia (Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany ) ; Juhász, Szilvia (Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany ) ; Künzel, Julia (Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany ) ; Spies, Julian (Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany ) ; Shibata, Atsushi (Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK ) ; Jeggo, Penny A. (Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK ) ; Löbrich, Markus (Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany ) ;
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    Summary Canonical non-homologous end joining (c-NHEJ) repairs DNA double-strand breaks (DSBs) in G1 cells with biphasic kinetics. We show that DSBs repaired with slow kinetics, including those localizing to heterochromatic regions or harboring additional lesions at the DSB site, undergo resection prior to repair by c-NHEJ and not alt-NHEJ. Resection-dependent c-NHEJ represents an inducible process during which Plk3 phosphorylates CtIP, mediating its interaction with Brca1 and promoting the initiation of resection. Mre11 exonuclease, EXD2, and Exo1 execute resection, and Artemis endonuclease functions to complete the process. If resection does not commence, then repair can ensue by c-NHEJ, but when executed, Artemis is essential to complete resection-dependent c-NHEJ. Additionally, Mre11 endonuclease activity is dispensable for resection in G1. Thus, resection in G1 differs from the process in G2 that leads to homologous recombination. Resection-dependent c-NHEJ significantly contributes to the formation of deletions and translocations in G1, which represent important initiating events in carcinogenesis. Highlights DSBs in G1 are repaired by resection-independent or resection-dependent c-NHEJ Resection-dependent c-NHEJ is induced by Plk3-dependent CtIP interaction with Brca1 G1 resection is executed from DSB ends by Mre11 exo, EXD2, and Exo1, but not Mre11 endo Artemis completes resection in G1, forming deletions and, potentially, translocations Graphical Abstract [DISPLAY OMISSION]


  • 주제어

    DNA double-strand breaks .   non-homologous end joining .   resection .   nucleases.  

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