title: Non-redundant Functions of ATM and DNA-PKcs in Response to DNA Double-Strand Breaks.
abstract: DNA double-strand breaks (DSBs) elicit the so-called DNA damage response (DDR), largely relying on ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PKcs), two members of the PI3K-like kinase family, whose respective functions during the sequential steps of the DDR remains controversial. Using the DIvA system (DSB inducible via AsiSI) combined with high-resolution mapping and advanced microscopy, we uncovered that both ATM and DNA-PKcs spread in cis on a confined region surrounding DSBs, independently of the pathway used for repair. However, once recruited, these kinases exhibit non-overlapping functions on end joining and γH2AX domain establishment. More specifically, we found that ATM is required to ensure the association of multiple DSBs within "repair foci." Our results suggest that ATM acts not only on chromatin marks but also on higher-order chromatin organization to ensure repair accuracy and survival.
authors.affiliation: Université de Toulouse, UPS, LBCMCP, 118 route de Narbonne, 31062 Toulouse, France; CNRS, LBCMCP, 31062 Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Caron
authors.affiliation: Université de Toulouse, UPS, LBCMCP, 118 route de Narbonne, 31062 Toulouse, France; CNRS, LBCMCP, 31062 Toulouse, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Choudjaye
authors.affiliation: Université de Toulouse, UPS, LBCMCP, 118 route de Narbonne, 31062 Toulouse, France; CNRS, LBCMCP, 31062 Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clouaire
authors.affiliation: Université de Toulouse, UPS, LBCMCP, 118 route de Narbonne, 31062 Toulouse, France; CNRS, LBCMCP, 31062 Toulouse, France.
authors.forename: Béatrix
authors.initials: B
authors.lastname: Bugler
authors.affiliation: Université de Toulouse, UPS, LBCMCP, 118 route de Narbonne, 31062 Toulouse, France; CNRS, LBCMCP, 31062 Toulouse, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Daburon
authors.affiliation: Université de Toulouse, UPS, LBCMCP, 118 route de Narbonne, 31062 Toulouse, France; CNRS, LBCMCP, 31062 Toulouse, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Aguirrebengoa
authors.affiliation: Université de Toulouse, UPS, LBCMCP, 118 route de Narbonne, 31062 Toulouse, France; CNRS, LBCMCP, 31062 Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mangeat
authors.affiliation: Bioinformatic Plateau I2MC, INSERM and University of Toulouse, 1 Avenue Jean Poulhes, BP 84225, 31432 Toulouse Cedex 4, France.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Iacovoni
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla, Sevilla 41092, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Álvarez-Quilón
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla, Sevilla 41092, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Cortés-Ledesma
authors.affiliation: Université de Toulouse, UPS, LBCMCP, 118 route de Narbonne, 31062 Toulouse, France; CNRS, LBCMCP, 31062 Toulouse, France. Electronic address: gaelle.legube@univ-tlse3.fr.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Legube
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D004247:DNA; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase
keywords: ChIP-chip; DSB repair; PI 3-kinases; chromatin; γH2AX