title: ATM regulates ATR chromatin loading in response to DNA double-strand breaks.
abstract: DNA double-strand breaks (DSBs) are among the most deleterious lesions that can challenge genomic integrity. Concomitant to the repair of the breaks, a rapid signaling cascade must be coordinated at the lesion site that leads to the activation of cell cycle checkpoints and/or apoptosis. In this context, ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR) protein kinases are the earliest signaling molecules that are known to initiate the transduction cascade at damage sites. The current model places ATM and ATR in separate molecular routes that orchestrate distinct pathways of the checkpoint responses. Whereas ATM signals DSBs arising from ionizing radiation (IR) through a Chk2-dependent pathway, ATR is activated in a variety of replication-linked DSBs and leads to activation of the checkpoints in a Chk1 kinase-dependent manner. However, activation of the G2/M checkpoint in response to IR escapes this accepted paradigm because it is dependent on both ATM and ATR but independent of Chk2. Our data provides an explanation for this observation and places ATM activity upstream of ATR recruitment to IR-damaged chromatin. These data provide experimental evidence of an active cross talk between ATM and ATR signaling pathways in response to DNA damage.
authors.affiliation: Genomic Instability Group, Spanish National Cancer Center, Madrid 28029, Spain.
authors.forename: Myriam
authors.initials: M
authors.lastname: Cuadrado
authors.forename: Barbara
authors.initials: B
authors.lastname: Martinez-Pastor
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.forename: Luis I
authors.initials: LI
authors.lastname: Toledo
authors.forename: Paula
authors.initials: P
authors.lastname: Gutierrez-Martinez
authors.forename: Eva
authors.initials: E
authors.lastname: Lopez
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
mesh_terms: D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D002843:Chromatin / Q000378:metabolism*; D019457:Chromosome Breakage / Q000235:genetics*; D004249:DNA Damage / Q000502:physiology*; D004261:DNA Replication / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000502:physiology*; D005434:Flow Cytometry; D005720:Gamma Rays; D006801:Humans; D010766:Phosphorylation / Q000528:radiation effects; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases