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

Monica Morales, Yan Liu, Evagelia C. Laiakis, William F. Morgan, Stephen D. Nimer, John H.J. Petrini

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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 Rad50S allele encodes a variant of Rad50, a member of the Mre11 complex. Cells expressing Rad50S 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 Rad50S/S mice, enhanced LSK proliferation triggers apoptotic attrition. This phenotype is mitigated when Rad50S/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 Rad50S pathology. We show that cells from Rad50S/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 Rad50S/S hematopoietic cells results from enhanced proliferation in the context of topoisomerase-associated DNA damage. Impairment of apoptosis in Rad50S/S mice promotes hematopoietic malignancy, suggesting that primitive hematopoietic cells serve as a reservoir of potentiallyo ncogenic lesions in Rad50S/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.

Original languageEnglish (US)
Pages (from-to)2186-2193
Number of pages8
JournalCancer Research
Volume68
Issue number7
DOIs
StatePublished - Apr 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'DNA damage signaling in hematopoietic cells: A role for Mre11 complex repair of topoisomerase lesions'. Together they form a unique fingerprint.

  • Cite this