The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor.
Genetic and cytologic data from Saccharomyces cerevisiae and mammals implicate the Mre11 complex, consisting of Mre11, Rad50, and Nbs1, as a sensor of DNA damage, and indicate that the complex influences the activity of ataxia-telangiectasia mutated (ATM) in the DNA damage response. Rad50(S/S) mice exhibit precipitous apoptotic attrition of hematopoietic cells. We generated ATM- and Chk2-deficient Rad50(S/S) mice and found that Rad50(S/S) cellular attrition was strongly ATM and Chk2 dependent. The hypomorphic Mre11(ATLD1) and Nbs1(Delta)(B) alleles conferred similar rescue of Rad50(S/S)-dependent hematopoietic failure. These data indicate that the Mre11 complex activates an ATM-Chk2-dependent apoptotic pathway. We find that apoptosis and cell cycle checkpoint activation are parallel outcomes of the Mre11 complex-ATM pathway. Conversely, the Rad50(S) mutation mitigated several phenotypic features of ATM deficiency. We propose that the Rad50(S) allele is hypermorphic for DNA damage signaling, and that the resulting constitutive low-level activation of the DNA damage response accounts for the partial suppression of ATM deficiency in Rad50(S/S) Atm(-/-) mice.
Morales
Monica
M
Molecular Biology Program, Memorial Sloan Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, New York 10021, USA.
Theunissen
Jan-Willem F
JW
Kim
Carla F Bender
CF
Kitagawa
Risa
R
Kastan
Michael B
MB
Petrini
John H J
JH
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D017766:Acid Anhydride Hydrolases; D000483:Alleles; D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D000076228:MRE11 Homologue Protein; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse; D045643:DNA Repair Enzymes