title: ATM specifically mediates repair of double-strand breaks with blocked DNA ends.
abstract: Ataxia telangiectasia is caused by mutations in ATM and represents a paradigm for cancer predisposition and neurodegenerative syndromes linked to deficiencies in the DNA-damage response. The role of ATM as a key regulator of signalling following DNA double-strand breaks (DSBs) has been dissected in extraordinary detail, but the impact of this process on DSB repair still remains controversial. Here we develop novel genetic and molecular tools to modify the structure of DSB ends and demonstrate that ATM is indeed required for efficient and accurate DSB repair, preventing cell death and genome instability, but exclusively when the ends are irreversibly blocked. We therefore identify the nature of ATM involvement in DSB repair, presenting blocked DNA ends as a possible pathogenic trigger of ataxia telangiectasia and related disorders.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla (Departamento de Genética), 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 (Departamento de Genética), Sevilla 41092, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Serrano-Benítez
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla (Departamento de Genética), Sevilla 41092, Spain.
authors.forename: Jenna Ariel
authors.initials: JA
authors.lastname: Lieberman
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla (Departamento de Genética), Sevilla 41092, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Quintero
authors.affiliation: Instituto Biomedicina Sevilla (IBiS), Hospital Virgen del Rocío-CSIC-Universidad de Sevilla (Departamento de Biología Celular), Sevilla 41013, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sánchez-Gutiérrez
authors.affiliation: Instituto Biomedicina Sevilla (IBiS), Hospital Virgen del Rocío-CSIC-Universidad de Sevilla (Departamento de Biología Celular), Sevilla 41013, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Escudero
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla (Departamento de Genética), Sevilla 41092, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Cortés-Ledesma
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008957:Models, Genetic; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C475961:gamma-H2AX protein, mouse; D004247:DNA; D064007:Ataxia Telangiectasia Mutated Proteins; D010727:Phosphoric Diester Hydrolases; C576816:TDP2 protein, mouse; D004250:DNA Topoisomerases, Type II