School of Biology, Georgia Institute of Technology, Atlanta, GA, USA.
Cell Cycle. 2011 Sep 1;10(17):3016-30. doi: 10.4161/cc.10.17.17543.
Cellular aging is linked to deficiencies in efficient repair of DNA double strand breaks and authentic genome maintenance at the chromatin level. Aging poses a significant threat to adult stem cell function by triggering persistent DNA damage and ultimately cellular senescence. Senescence is often considered to be an irreversible process. Moreover, critical genomic regions engaged in persistent DNA damage accumulation are unknown. Here we report that 65% of naturally occurring repairable DNA damage in self-renewing adult stem cells occurs within transposable elements. Upregulation of Alu retrotransposon transcription upon ex vivo aging causes nuclear cytotoxicity associated with the formation of persistent DNA damage foci and loss of efficient DNA repair in pericentric chromatin. This occurs due to a failure to recruit of condensin I and cohesin complexes. Our results demonstrate that the cytotoxicity of induced Alu repeats is functionally relevant for the human adult stem cell aging. Stable suppression of Alu transcription can reverse the senescent phenotype, reinstating the cells' self-renewing properties and increasing their plasticity by altering so-called "master" pluripotency regulators.
细胞衰老与 DNA 双链断裂的有效修复以及染色质水平上真实基因组的维持缺陷有关。衰老通过引发持续的 DNA 损伤并最终导致细胞衰老，对成体干细胞功能构成重大威胁。衰老通常被认为是一个不可逆的过程。此外，参与持续 DNA 损伤积累的关键基因组区域尚不清楚。在这里，我们报告说，自我更新的成体干细胞中 65%的自然发生的可修复 DNA 损伤发生在转座元件内。衰老过程中外显 Alu 逆转录转座子转录的上调导致核细胞毒性，与持续 DNA 损伤焦点的形成和中心粒染色质中有效 DNA 修复的丧失有关。这是由于无法募集凝聚素 I 和黏合蛋白复合物。我们的研究结果表明，诱导的 Alu 重复的细胞毒性对于人类成体干细胞衰老具有功能相关性。Alu 转录的稳定抑制可以逆转衰老表型，通过改变所谓的“主”多能性调节因子，恢复细胞的自我更新特性并增加其可塑性。
