Journal
CELLS
Volume 10, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/cells10030550
Keywords
cell cycle; checkpoint; CDKs; DNA damage; recovery; G1; CDK4; CDK6
Categories
Funding
- Netherlands Genomic Initiative of the Netherlands Organization for Scientific Research (NWO) (Cancer Genomics Center.nl)
- Top-Go ZonMw [91210065]
- Oncode Institute
- Dutch Cancer Society [NKI 2009-4478, NKI 2011-5215, NKI2014-6787]
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Most Cdks are redundant for normal cell division, but become essential for S-phase entry after DNA damage in G1. In damaged cells, high levels of Cdk4/6 activity are required to inactivate pocket proteins and APC/C-Cdh1 to promote the transition from G1 to S phase.
Most Cyclin-dependent kinases (Cdks) are redundant for normal cell division. Here we tested whether these redundancies are maintained during cell cycle recovery after a DNA damage-induced arrest in G1. Using non-transformed RPE-1 cells, we find that while Cdk4 and Cdk6 act redundantly during normal S-phase entry, they both become essential for S-phase entry after DNA damage in G1. We show that this is due to a greater overall dependency for Cdk4/6 activity, rather than to independent functions of either kinase. In addition, we show that inactivation of pocket proteins is sufficient to overcome the inhibitory effects of complete Cdk4/6 inhibition in otherwise unperturbed cells, but that this cannot revert the effects of Cdk4/6 inhibition in DNA damaged cultures. Indeed, we could confirm that, in addition to inactivation of pocket proteins, Cdh1-dependent anaphase-promoting complex/cyclosome (APC/C-Cdh1) activity needs to be inhibited to promote S-phase entry in damaged cultures. Collectively, our data indicate that DNA damage in G1 creates a unique situation where high levels of Cdk4/6 activity are required to inactivate pocket proteins and APC/C-Cdh1 to promote the transition from G1 to S phase.
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