DNA damage signaling in hematopoietic cells: A role for Mre11 complex repair of topoisomerase lesions

The Mre11 complex promotes DNA double-strand break repair and regulates DNA damage signaling via activation of the ataxia-telangiectasia mutated (ATM) kinase. The hypermorphic Rad50^S allele encodes a variant of Rad50, a member of the Mre11 complex. Cells expressing Rad50^S experience constitutive ATM activation, which leads to precipitous apoptotic attrition in hematopoietic cells. In this study, we show that ATM activation bythe Rad50S-containing Mre11 complex enhances the proliferation of LSK cells, a population consisting of hematopoietic stem cells and multipotent progenitor cells. In Rad50^S/S mice, enhanced LSK proliferation triggers apoptotic attrition. This phenotype is mitigated when Rad50^S/S is combined with mutations that alter either LSK cell quiescence (myeloid elf-1-like factor/ELF4-deficient mice) or hematopoietic differentiation (p21- and p27-deficient mice), indicating that the LSK population is a primary target of Rad50^S pathology. We show that cells from Rad50^S/S mice are hypersensitive to camptothecin, a topoisomerase I inhibitor that causes DNA damage primarilyduring DNA replication. On this basis, we propose that apoptotic attrition of Rad50^S/S hematopoietic cells results from enhanced proliferation in the context of topoisomerase-associated DNA damage. Impairment of apoptosis in Rad50^S/S mice promotes hematopoietic malignancy, suggesting that primitive hematopoietic cells serve as a reservoir of potentiallyo ncogenic lesions in Rad50^S/S mice. These data provide compelling evidence that the Mre11 complex plays a role in the metabolism of topoisomerase lesions in mammals, and further suggest that such lesions can accumulate in primitive hematopoietic cells and confer significant oncogenic potential.