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

¹ Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences; ² Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York; and ³ Radiation Oncology Research Laboratory and ⁴ Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland

Requests for reprints: John H.J. Petrini, Laboratory of Chromosome Biology, Memorial Sloan-Kettering Cancer Center, RRL 901C, Box 474, 1275 York Avenue, New York, NY 10021. Phone: 212-639-2927; Fax: 646-422-2062; E-mail: petrinij{at}mskcc.org.

Key Words: Hematopoietic stem cell • Quiescence • Mre11 complex • DNA damage signaling • tumorigenesis

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 by the 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 primarily during 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 potentially oncogenic 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. [Cancer Res 2008;68(7):2186–93]