Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice.
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.
Schaetzlein
Sonja
S
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, 30625 Hanover, Germany.
Kodandaramireddy
N R
NR
Ju
Zhenyu
Z
Lechel
Andre
A
Stepczynska
Anna
A
Lilli
Dana R
DR
Clark
Alan B
AB
Rudolph
Cornelia
C
Kuhnel
Florian
F
Wei
Kaichun
K
Schlegelberger
Brigitte
B
Schirmacher
Peter
P
Kunkel
Thomas A
TA
Greenberg
Roger A
RA
Edelmann
Winfried
W
Rudolph
K Lenhard
KL
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