Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Cell Death Differ. 2010 Jul;17(7):1189-98. doi: 10.1038/cdd.2009.221. Epub 2010 Jan 29.
It is commonly believed that neurons remain in G(0) phase of the cell cycle indefinitely. Cell-cycle re-entry, however, is known to contribute to neuronal apoptosis. Moreover, recent evidence demonstrates the expression of cell-cycle proteins in differentiated neurons under physiological conditions. The functional roles of such expression remain unclear. Since DNA repair is generally attenuated by differentiation in most cell types, the cell-cycle-associated events in postmitotic cells may reflect the need to re-enter the cell cycle to activate DNA repair. We show that cyclin-C-directed, pRb-dependent G(0) exit activates the non-homologous end joining pathway of DNA repair (NHEJ) in postmitotic neurons. Using RNA interference, we found that abrogation of cyclin-C-mediated exit from G(0) compromised DNA repair but did not initiate apoptosis. Forced G(1) entry combined with prevention of G(1) --> S progression triggered NHEJ activation even in the absence of DNA lesions, but did not induce apoptosis in contrast to unrestricted progression through G(1) --> S. We conclude that G(0) --> G(1) transition is functionally significant for NHEJ repair in postmitotic neurons. These findings reveal the importance of cell-cycle activation for controlling both DNA repair and apoptosis in postmitotic neurons, and underline the particular role of G(1) --> S progression in apoptotic signaling, providing new insights into the mechanisms of DNA damage response (DDR) in postmitotic neurons.
人们普遍认为神经元会无限期地停留在细胞周期的 G(0)期。然而，细胞周期重新进入已经被证实会导致神经元凋亡。此外，最近的证据表明，在生理条件下，细胞周期蛋白会在分化神经元中表达。这种表达的功能作用尚不清楚。由于在大多数细胞类型中，DNA 修复通常会随着分化而减弱，因此有丝分裂后细胞中的细胞周期相关事件可能反映了重新进入细胞周期以激活 DNA 修复的需要。我们发现，由 cyclin-C 指导的、pRb 依赖性的 G(0)期退出会激活有丝分裂后神经元中的非同源末端连接（NHEJ）途径的 DNA 修复。通过 RNA 干扰，我们发现，阻断 cyclin-C 介导的 G(0)期退出会损害 DNA 修复，但不会引发凋亡。强制进入 G(1)期并阻止 G(1) --> S 期进展，即使在没有 DNA 损伤的情况下，也会触发 NHEJ 激活，但与不受限制地通过 G(1) --> S 期进展不同，不会诱导凋亡。我们得出结论，G(0) --> G(1) 转换对于有丝分裂后神经元中的 NHEJ 修复具有功能意义。这些发现揭示了细胞周期激活对于控制有丝分裂后神经元中的 DNA 修复和凋亡的重要性，并强调了 G(1) --> S 期进展在凋亡信号中的特殊作用，为有丝分裂后神经元中的 DNA 损伤反应（DDR）机制提供了新的见解。
