The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
BMC Biol. 2010 Oct 27;8:132. doi: 10.1186/1741-7007-8-132.
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.
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.
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.
未修复的 DNA 双链断裂（DSBs）会导致染色体重排、遗传信息丢失、肿瘤转化或细胞死亡。非同源末端连接（NHEJ）途径通过催化 DSBs 的无序列依赖性直接连接，是修复随机发生和发育编程 DSBs 的关键机制。在淋巴细胞中，NHEJ 对于发育和基因组稳定性至关重要。NHEJ 缺陷会导致严重联合免疫缺陷（SCID）和淋巴癌易感性，无论是在小鼠还是人类中都是如此。虽然 NHEJ 在淋巴细胞中已经得到了深入研究，但 NHEJ 在其他细胞类型中的重要性，特别是在肿瘤抑制方面，记录较少。我们之前报道的证据表明，NHEJ 途径通过未知机制发挥作用，抑制一系列非淋巴肿瘤类型，包括各种类别的肉瘤。
在这里，我们研究了 NHEJ 因子 ARTEMIS 在多能间充质干细胞/祖细胞（MSCs）中的作用，MSCs 是潜在的肉瘤发生细胞。我们在一个敏感的小鼠肿瘤模型中证明了 ARTEMIS 在抑制肉瘤中的关键作用。在这种情况下，我们发现 ARTEMIS 缺陷导致了染色体损伤，但矛盾的是，在经受各种应激的原代 MSCs 中，增强了其抵抗能力和增殖潜力。基因表达分析显示，ARTEMIS 缺陷的 MSC 中异常调节了应激反应、细胞增殖和信号转导途径。最后，我们确定了候选调节基因，这些基因可能部分介导了 ARTEMIS 缺陷的前肿瘤 MSC 中的应激抵抗、过度增殖表型。
我们的发现表明 Art 可防止暴露于各种应激刺激的 MSC 中的基因组损伤并抑制其增殖。我们提出，缺陷导致原代 MSCs 处于前肿瘤状态，并与异常的增殖控制和细胞应激抵抗相关。因此，我们的数据揭示了 ARTEMIS 和 NHEJ 途径在正常 MSC 功能中的惊人新作用，以及与间质组织中肿瘤抑制相关的 MSC 适应性和适宜性。
