artemis stabilizes the genome and modulates proliferative responses in multipotent mesenchymal cells阿耳特弥斯基因组稳定和调节多能的间充质细胞的增殖反应.pdfVIP

Maas et al. BMC Biology 2010, 8:132 /1741-7007/8/132 RESEARCH ARTICLE Open Access ARTEMIS stabilizes the genome and modulates proliferative responses in multipotent mesenchymal cells 1,2† 1† 1,3 4 1,5* Sarah A Maas , Nina M Donghia , Kathleen Tompkins , Oded Foreman , Kevin D Mills 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, ce