Abstract
It is commonly believed that neurons remain in G0 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 G0 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 G0 compromised DNA repair but did not initiate apoptosis. Forced G1 entry combined with prevention of G1 → S progression triggered NHEJ activation even in the absence of DNA lesions, but did not induce apoptosis in contrast to unrestricted progression through G1 → S. We conclude that G0 → G1 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 G1 → S progression in apoptotic signaling, providing new insights into the mechanisms of DNA damage response (DDR) in postmitotic neurons.
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Abbreviations
- CDK:
-
cyclin-dependent kinase
- CKI:
-
cyclin-dependent kinase inhibitor
- DNA–PKcs:
-
DNA–protein-kinase catalytic subunit
- DSB:
-
double-strand break
- NHEJ:
-
non-homologous end joining
- pRb:
-
retinoblastoma protein
- siRNA:
-
small interfering RNA
- DDR:
-
DNA damage response
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Acknowledgements
We thank Raul Perez-Olle for helpful discussions and P Makhov for the pGL3 basic vector. This work was supported by the Garrison Institute on Aging, TTUHSC. MG was funded by the NIA-IRP, NIH.
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Tomashevski, A., Webster, D., Grammas, P. et al. Cyclin-C-dependent cell-cycle entry is required for activation of non-homologous end joining DNA repair in postmitotic neurons. Cell Death Differ 17, 1189–1198 (2010). https://doi.org/10.1038/cdd.2009.221
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DOI: https://doi.org/10.1038/cdd.2009.221
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