title: DNA Double-Strand Break Resection Occurs during Non-homologous End Joining in G1 but Is Distinct from Resection during Homologous Recombination.
abstract: 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.
authors.affiliation: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Biehs
authors.affiliation: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Steinlage
authors.affiliation: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors.forename: Olivia
authors.initials: O
authors.lastname: Barton
authors.affiliation: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors.forename: Szilvia
authors.initials: S
authors.lastname: Juhász
authors.affiliation: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Künzel
authors.affiliation: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Spies
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK; Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan. Electronic address: shibata.at@gunma-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shibata
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK. Electronic address: p.a.jeggo@sussex.ac.uk.
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
authors.affiliation: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany. Electronic address: lobrich@bio.tu-darmstadt.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Löbrich
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000528:radiation effects*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000528:radiation effects*; D016195:G2 Phase; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D000097868:Polo-like Kinases
chemical_list: D019313:BRCA1 Protein; D002352:Carrier Proteins; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C492913:BRCA1 protein, human; C121766:MRE11 protein, human; C498301:TP53BP1 protein, human; C486256:PLK3 protein, human; D000097868:Polo-like Kinases; C426344:DCLRE1C protein, human; C114331:EXO1 protein, human; C410741:RBBP8 protein, human
keywords: DNA double-strand breaks; non-homologous end joining; nucleases; resection