The Rad50^S 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 Rad50 S/S mice and found that Rad50 S/S cellular attrition was strongly ATM and Chk2 dependent. The hypomorphic Mre11 ATLD1 and Nbs1 ⌬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.[Keywords: Checkpoints; DNA damage signaling; apoptosis]Supplemental material is available at http://www.genesdev.org.

The Rad50 hook domain regulates DNA damage signaling and tumorigenesis

“…The Rad50 +/46 phenotype is ATM-dependent Precedent for the hypothesis that Rad50 +/46 phenotypes could be ATM-dependent comes from Rad50 S/S mice, which at both the cellular and organismal levels exhibited phenotypes reminiscent of Rad50 +/46 (Bender et al 2002;Morales et al 2005). We found that most aspects of the Rad50 +/46 pathology, including hydrocephalus ( Fig.…”

“…A remarkable outcome in Rad50 S/S Atm À/À mice was the suppression of lymphomagenesis associated to ATM deficiency (Morales et al 2005;Usui et al 2006). Similarly, the latency of thymic lymphomas typical of the (Theunissen et al 2003).…”

“…P-values were determined by unpaired t-test. (D) Kaplan-Meier survival curves of Atm À/À , Rad50 S/S , Rad50 S/S Atm À/À (previously published; Morales et al 2005), Rad50 +/46 , and Rad50 +/46 Atm À/À mice. Rad50 +/46 mouse survival was not assessed beyond 18 mo, and thus the events were censored at that age.…”

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

“…BRG1 and senescence of mesenchymal stem cells N Alessio et al Morales et al (2005), who showed that overexpression of RAD50, a member of the MRE11 DNA repair complex, produced excess DNA damage signaling that compromised the functioning of hematopoietic stem cells. Forced BRG1 expression induced an increase in the number of apoptotic cells, whereas silencing caused a significant reduction in cells undergoing programmed cell death (Figure 2c; Napolitano et al, 2007).…”

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

“…Moreover, hematopoietic progenitor numbers and proliferative reserves were dramatically decreased in the Ercc1-/-mice compared to their wild type counterparts. Defects in hematopoietic stem cell (HSC) function were also described in Fancd1, Msh2, and Rad50-deficient mice (Morales et al, 2005;Navarro et al, 2006;Reese et al, 2003). In other recent experiments, Ninjik et al (Nijnik et al, 2007) and Rossi et al (Rossi et al, 2007), examining various DNA repair or telomerase-deficient mouse strains (Lig4, Ku80, Xpd, and mTR), showed that hematopoietic stem cells declined rapidly in functionality with age, if not in number.…”