Cyclin-C-dependent cell-cycle entry is required for activation of non-homologous end joining DNA repair in postmitotic neurons.
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.
Tomashevski
A
A
Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Webster
D R
DR
Grammas
P
P
Gorospe
M
M
Kruman
I I
II
D017209:Apoptosis; D002453:Cell Cycle; D056745:Cyclin C / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D016193:G1 Phase; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D016160:Retinoblastoma Protein / Q000378:metabolism
D056745:Cyclin C; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D006861:Hydrogen Peroxide