DNA damage signaling in hematopoietic cells: A role for Mre11 complex repair of topoisomerase lesions Journal Article
| Authors: | Morales, M.; Liu, Y.; Laiakis, E. C.; Morgan, W. F.; Nimer, S. D.; Petrini, J. H. J. |
| Article Title: | DNA damage signaling in hematopoietic cells: A role for Mre11 complex repair of topoisomerase lesions |
| 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. ©2008 American Association for Cancer Research. |
| Keywords: | signal transduction; unclassified drug; dna binding protein; dna-binding proteins; nonhuman; flow cytometry; dna replication; cell proliferation; animal cell; mouse; phenotype; animals; mice; mre11 protein; rad50 protein; dna damage; atp-binding cassette transporters; dna repair; apoptosis; animal experiment; mice, mutant strains; camptothecin; mice, inbred c57bl; cell lineage; hematologic neoplasms; protein p27; hematopoietic cell; hematopoietic stem cells; atm protein; dna repair enzymes; dna topoisomerase inhibitor; multipotent stem cell; p21 activated kinase; protein elf4; transcription factor elf 1; dna topoisomerases |
| Journal Title: | Cancer Research |
| Volume: | 68 |
| Issue: | 7 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-04-01 |
| Start Page: | 2186 |
| End Page: | 2193 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-07-2355 |
| PUBMED: | 18381424 |
| PROVIDER: | scopus |
| PMCID: | PMC2996041 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 17 November 2011" - "CODEN: CNREA" - "Source: Scopus" |
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