Cancer predisposition and hematopoietic failure in Rad50^S/S mice

Abstract

Mre11, Rad50, and Nbs1 function in a protein complex that is central to the metabolism of chromosome breaks. Null mutants of each are inviable. We demonstrate here that hypomorphic Rad50 mutant mice (Rad50 S/S mice) exhibited growth defects and cancer predisposition. Rad50 S/S mice died with complete bone marrow depletion as a result of progressive hematopoietic stem cell failure. Similar attrition occurred in spermatogenic cells. In both contexts, attrition was substantially mitigated by p53 deficiency, whereas the tumor latency of p53 −/− and p53 +/− animals was reduced by Rad50 S/S . Indices of genotoxic stress and chromosomal rearrangements were evident in Rad50 S/S cultured cells, as well as in Rad50 S/S and p53 −/− Rad50 S/S lymphomas, suggesting that the Rad50 S/S phenotype was attributable to chromosomal instability. These outcomes were not associated with overt defects in the Mre11 complex's previously established double strand break repair and cell cycle checkpoint regulation functions. The data indicate that even subtle perturbation of Mre11 complex functions results in severe genotoxic stress, and that the complex is critically important for homeostasis of proliferative tissues.

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.…”

“…MEFs and EFs were generated, cultured, and immortalized as described (Bender et al 2002). Rad50 +/47 EFs were generated from Rad50 +/Neo47 chimeric mice by growing the cells in medium containing 1 mg/mL G418 followed by lentiviral delivery of Cre and clonal selection.…”

Genome-wide RNAi identifies p53-dependent and -independent regulators of germ cell apoptosis in C. elegans

“…Similarly, mice carrying a mutation in either Rad50 or Rad51 show increased apoptosis. 11,12 Moreover, it has recently been reported that inactivation of the p53 inhibitor iASPP, and its worm counterpart ape-1, induces apoptosis in a p53-dependent manner. 13 We independently identified ape-1 in our RNAi screen, and confirmed that its inactivation requires p53 to cause a Gla phenotype (Table 1 and see below).…”

The multiple roles of the Mre11 complex for meiotic recombination

“…Thus, the Rad50K22M allele (equivalent to yeast R20M) was studied (Figure 1). The FRad50S_ mice showed not much meiotic phenotype, and were fertile: although there was a cellular attrition in testes, there was no meiotic recombination defect, normal meiotic progression and chromosome morphology (Bender et al 2002). Amazingly, these mice showed almost no cellular phenotype, unlike the other Mre11 complex hypomorphic mutations: cells were not sensitive to DNA damage and showed no radioresistant DNA synthesis (RDS).…”

“…Amazingly, these mice showed almost no cellular phenotype, unlike the other Mre11 complex hypomorphic mutations: cells were not sensitive to DNA damage and showed no radioresistant DNA synthesis (RDS). There were wild-type levels of protein, but a profound impact on the organismal level (Bender et al 2002). In these mutants there is a constitutive damage (increase of chromosome breakage and constitutive histone H2AX phosphorylation) (Bender et al 2002) and a constitutive activation of PIPK3 kinases, probably due to unprocessed Fphysiological_ damage (Bender et al 2002, Morales et al 2005).…”