The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: Implications for the Mre11 complex as a DNA damage sensor Journal Article

   

Authors:	Morales, M.; Theunissen, J. W. F.; Bender Kim, C. F.; Kitagawa, R.; Kastan, M. B.; Petrini, J. H. J.
Article Title:	The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: Implications for the Mre11 complex as a DNA damage sensor
Abstract:	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 Rad50S/S mice and found that Rad50S/S cellular attrition was strongly ATM and Chk2 dependent. The hypomorphic Mre11ATLD1 and Nbs1ΔB alleles conferred similar rescue of Rad50S/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 Rad50S mutation mitigated several phenotypic features of ATM deficiency. We propose that the Rad50S 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 Rad50S/S Atm-/- mice. © 2005 by Cold Spring Harbor Laboratory Press.
Keywords:	signal transduction; controlled study; dna binding protein; genetics; dna-binding proteins; nonhuman; protein function; cell cycle protein; animal cell; mouse; animal; cytology; metabolism; mouse mutant; mammalia; animals; cell cycle proteins; mice; mice, knockout; mre11 protein; rad50 protein; allele; dna damage; atp-binding cassette transporters; cells, cultured; complex formation; apoptosis; protein; alleles; enzyme activity; protein serine threonine kinase; animalia; nibrin; gene expression regulation; cell culture; saccharomyces cerevisiae; protein-serine-threonine kinases; mammal; tumor suppressor proteins; abc transporter; hematopoietic cell; hematopoietic stem cells; atm protein; dna repair enzymes; hematopoiesis; checkpoint kinase 2; hematopoietic stem cell; polydeoxyribonucleotide synthase; tumor suppressor protein; mutagenesis; knockout mouse; checkpoints; ataxia telangiectasia; mre11a protein, mouse; rad50 protein, mouse; dna damage signaling
Journal Title:	Genes and Development
Volume:	19
Issue:	24
ISSN:	0890-9369
Publisher:	Cold Spring Harbor Laboratory Press
Date Published:	2005-12-15
Start Page:	3043
End Page:	3054
Language:	English
DOI:	10.1101/gad.1373705
PUBMED:	16357220
PROVIDER:	scopus
PMCID:	PMC1315407
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-29144450333&partnerID=40&md5=cdc11458c4033be174affc94c2be2fe8
Notes:	--- - "Cited By (since 1996): 56" - "Export Date: 24 October 2012" - "CODEN: GEDEE" - "Source: Scopus"

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