ARTEMIS stabilizes the genome and modulates proliferative responses in multipotent mesenchymal cells

Public Deposited
Analytics

Downloadable Content

Download PDF
Request Version for Screen Reader
Creator
  • Maas, Sarah A
    • Other Affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor ME 04609, USA; Adnexus Therapeutics, Waltham, MA 02453, USA
  • Donghia, Nina M
    • Other Affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor ME 04609, USA
  • Tompkins, Kathleen
    • Affiliation: School of Medicine, Division of Infectious Diseases
    • Other Affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor ME 04609, USA
  • Foreman, Oded
    • Other Affiliation: The Jackson Laboratory, 4910 Raley Road, Sacramento CA, 95838, USA
  • Mills, Kevin D
    • Other Affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor ME 04609, USA; Main Medical Center Research Institute, Scarborough Maine, USA
Abstract
  • Abstract Background Unrepaired DNA double-stranded breaks (DSBs) cause chromosomal rearrangements, loss of genetic information, neoplastic transformation or cell death. The nonhomologous end joining (NHEJ) pathway, catalyzing sequence-independent direct rejoining of DSBs, is a crucial mechanism for repairing both stochastically occurring and developmentally programmed DSBs. In lymphocytes, NHEJ is critical for both development and genome stability. NHEJ defects lead to severe combined immunodeficiency (SCID) and lymphoid cancer predisposition in both mice and humans. While NHEJ has been thoroughly investigated in lymphocytes, the importance of NHEJ in other cell types, especially with regard to tumor suppression, is less well documented. We previously reported evidence that the NHEJ pathway functions to suppress a range of nonlymphoid tumor types, including various classes of sarcomas, by unknown mechanisms. Results Here we investigate roles for the NHEJ factor ARTEMIS in multipotent mesenchymal stem/progenitor cells (MSCs), as putative sarcomagenic cells of origin. We demonstrate a key role for ARTEMIS in sarcoma suppression in a sensitized mouse tumor model. In this context, we found that ARTEMIS deficiency led to chromosomal damage but, paradoxically, enhanced resistance and proliferative potential in primary MSCs subjected to various stresses. Gene expression analysis revealed abnormally regulated stress response, cell proliferation, and signal transduction pathways in ARTEMIS-defective MSCs. Finally, we identified candidate regulatory genes that may, in part, mediate a stress-resistant, hyperproliferative phenotype in preneoplastic ARTEMIS-deficient MSCs. Conclusions Our discoveries suggest that Art prevents genome damage and restrains proliferation in MSCs exposed to various stress stimuli. We propose that deficiency leads to a preneoplastic state in primary MSCs and is associated with aberrant proliferative control and cellular stress resistance. Thus, our data reveal surprising new roles for ARTEMIS and the NHEJ pathway in normal MSC function and fitness relevant to tumor suppression in mesenchymal tissues.
Date of publication
DOI
Identifier
Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Sarah A Maas et al.; licensee BioMed Central Ltd.
License
Journal title
  • BMC Biology
Journal volume
  • 8
Journal issue
  • 1
Page start
  • 132
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1741-7007
Bibliographic citation
  • BMC Biology. 2010 Oct 27;8(1):132
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • August 23, 2012

Relations

Parents:

This work has no parents.

Items

Thumbnail Title Date Uploaded Visibility Actions
file details 1741-7007-8-132.pdf 2019-05-07 Public Download
file details The _, encoding ARTEMIS, is transcribed in mesenchymal stem cells (MSCs) 2019-05-07 Public Download
file details Control for differentiation specificity of WT or MSCs 2019-05-07 Public Download
file details Photomicrograph of Art-null MSC culture following 6 days of serum withdrawal. 2019-05-07 Public Download
file details Photomicrograph of WT MSC culture following 2 days of serum withdrawal. 2019-05-07 Public Download
file details Photomicrograph of WT MSC culture following 6 days of serum withdrawal. 2019-05-07 Public Download
file details Photomicrograph of Art-null MSC culture following 2 days of serum withdrawal. 2019-05-07 Public Download
file details 1741-7007-8-132.xml 2019-05-07 Public Download
file details Aneuploidy without translocations in -null sarcomas 2019-05-07 Public Download