title: EXO1 is critical for embryogenesis and the DNA damage response in mice with a hypomorphic Nbs1 allele.
abstract: The maintenance of genome stability is critical for the suppression of diverse human pathologies that include developmental disorders, premature aging, infertility and predisposition to cancer. The DNA damage response (DDR) orchestrates the appropriate cellular responses following the detection of lesions to prevent genomic instability. The MRE11 complex is a sensor of DNA double strand breaks (DSBs) and plays key roles in multiple aspects of the DDR, including DNA end resection that is critical for signaling and DNA repair. The MRE11 complex has been shown to function both upstream and in concert with the 5'-3' exonuclease EXO1 in DNA resection, but it remains unclear to what extent EXO1 influences DSB responses independently of the MRE11 complex. Here we examine the genetic relationship of the MRE11 complex and EXO1 during mammalian development and in response to DNA damage. Deletion of Exo1 in mice expressing a hypomorphic allele of Nbs1 leads to severe developmental impairment, embryonic death and chromosomal instability. While EXO1 plays a minimal role in normal cells, its loss strongly influences DNA replication, DNA repair, checkpoint signaling and damage sensitivity in NBS1 hypomorphic cells. Collectively, our results establish a key role for EXO1 in modulating the severity of hypomorphic MRE11 complex mutations.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Katrin
authors.initials: K
authors.lastname: Rein
authors.affiliation: Department of Radiation Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Yanez
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Terré
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Palenzuela
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Suvi
authors.initials: S
authors.lastname: Aivio
authors.affiliation: Albert Einstein College of Medicine, Department of Cell Biology, Bronx, NY 10461, USA.
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wei
authors.affiliation: Albert Einstein College of Medicine, Department of Cell Biology, Bronx, NY 10461, USA.
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.affiliation: Department of Radiation Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Stark
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain Travis.Stracker@irbbarcelona.org.
authors.forename: Travis H
authors.initials: TH
authors.lastname: Stracker
mesh_terms: D000483:Alleles; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002166:Camptothecin / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D043171:Chromosomal Instability; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication; D004268:DNA-Binding Proteins; D047108:Embryonic Development / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000502:physiology*; D059565:G2 Phase Cell Cycle Checkpoints; D017353:Gene Deletion; D005804:Genes, Lethal; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C583623:Exo1 protein, mouse; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes; D002166:Camptothecin