title: Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice.
abstract: Exonuclease-1 (EXO1) mediates checkpoint induction in response to telomere dysfunction in yeast, but it is unknown whether EXO1 has similar functions in mammalian cells. Here we show that deletion of the nuclease domain of Exo1 reduces accumulation of DNA damage and DNA damage signal induction in telomere-dysfunctional mice. Exo1 deletion improved organ maintenance and lifespan of telomere-dysfunctional mice but did not increase chromosomal instability or cancer formation. Deletion of Exo1 also ameliorated the induction of DNA damage checkpoints in response to gamma-irradiation and conferred cellular resistance to 6-thioguanine-induced DNA damage. Exo1 deletion impaired upstream induction of DNA damage responses by reducing ssDNA formation and the recruitment of Replication Protein A (RPA) and ATR at DNA breaks. Together, these studies provide evidence that EXO1 contributes to DNA damage signal induction in mammalian cells, and deletion of Exo1 can prolong survival in the context of telomere dysfunction.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, 30625 Hanover, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schaetzlein
authors.forename: N R
authors.initials: NR
authors.lastname: Kodandaramireddy
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.forename: Andre
authors.initials: A
authors.lastname: Lechel
authors.forename: Anna
authors.initials: A
authors.lastname: Stepczynska
authors.forename: Dana R
authors.initials: DR
authors.lastname: Lilli
authors.forename: Alan B
authors.initials: AB
authors.lastname: Clark
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rudolph
authors.forename: Florian
authors.initials: F
authors.lastname: Kuhnel
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wei
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kunkel
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D043171:Chromosomal Instability; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005720:Gamma Rays; D017353:Gene Deletion; D050939:Gene Fusion; D005838:Genotype; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D008136:Longevity / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009153:Mutagens / Q000494:pharmacology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D051716:Replication Protein A / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D013866:Thioguanine / Q000494:pharmacology