Cyclin E1 and cyclin E2 can associate with and activate CDK2. Upon DNA damage, upregulation/activation of the CDK inhibitors p21 Waf1/Cip1 and p27 Kip1 prevent cyclin E/CDK2 activation, resulting in G1/S arrest. When conditions are favorable for cell cycle progression, cyclin D/CDK4/6 phosphorylates Rb and is thought to reduce the activity of p21 Waf1/Cip1 and p27 Kip1, allowing subsequent activation of cyclin E/CDK2. Cyclin E/CDK2 further phosphorylates Rb to allow progression into S-phase, where cyclin E/CDK2 is thought to phosphorylate and activate multiple proteins involved in DNA synthesis. Turnover of cyclin E is largely controlled by phosphorylation that results in SCFFbw7-mediated ubiquitination and proteasome-dependent degradation. Cyclin E1 is phosphorylated at multiple sites in vivo including Thr62, Ser88, Ser72, Thr380, and Ser384, and is controlled by at least two kinases, CDK2 and GSK-3.