Data from DNA Damage Signaling in Hematopoietic Cells: A Role for Mre11 Complex Repair of Topoisomerase Lesions

Abstract

<div>Abstract<p>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 <i>Rad50<sup>S</sup></i> allele encodes a variant of Rad50, a member of the Mre11 complex. Cells expressing <i>Rad50<sup>S</sup></i> experience constitutive ATM activation, which leads to precipitous apoptotic attrition in hematopoietic cells. In this study, we show that ATM activation by the <i>Rad50S</i>-containing Mre11 complex enhances the proliferation of LSK cells, a population consisting of hematopoietic stem cells and multipotent progenitor cells. In <i>Rad50<sup>S/S</sup></i> mice, enhanced LSK proliferation triggers apoptotic attrition. This phenotype is mitigated when <i>Rad50<sup>S/S</sup></i> 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 <i>Rad50<sup>S</sup></i> pathology. We show that cells from <i>Rad50<sup>S/S</sup></i> mice are hypersensitive to camptothecin, a topoisomerase I inhibitor that causes DNA damage primarily during DNA replication. On this basis, we propose that apoptotic attrition of <i>Rad50<sup>S/S</sup></i> hematopoietic cells results from enhanced proliferation in the context of topoisomerase-associated DNA damage. Impairment of apoptosis in <i>Rad50<sup>S/S</sup></i> mice promotes hematopoietic malignancy, suggesting that primitive hematopoietic cells serve as a reservoir of potentially oncogenic lesions in <i>Rad50<sup>S/S</sup></i> 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. [Cancer Res 2008;68(7):2186–93]</p></div>