Cyclin D1 is a component of the core cell cycle machinery1. Abnormally high levels of cyclin D1 are detected in many human cancer types2. To elucidate the molecular functions of cyclin D1 in human cancers, here we performed a proteomic screen for cyclin D1 protein partners in several types of human tumors. Analyses of cyclin D1-interactors revealed a network of DNA repair proteins, including RAD51, a recombinase that drives the homologous recombination process3. We found that cyclin D1 directly binds RAD51, and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein, which do not require D-cyclins for proliferation4, 5. These findings reveal an unexpected function of a core cell cycle protein in DNA repair and suggest that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers which are currently thought to be oblivious to cyclin D1 inhibition.

Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers1–3, and is closely associated with poor prognosis and chemo- or radio-therapeutic resistance4. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark7. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.

Cyclins, cyclin-dependent kinases and other components of the core cell cycle machinery drive cell division. Growing evidence indicates that this machinery operates in a distinct fashion in some mammalian stem cell types, such as pluripotent embryonic stem cells. In this review, we discuss our current knowledge of how cell cycle proteins mechanistically link cell proliferation, pluripotency and cell fate specification. We focus on embryonic stem cells, induced pluripotent stem cells, and embryonic neural stem/progenitor cells. The core cell cycle machinery operating in the cell nucleus orchestrates cell division. The key components of this machinery are proteins called cyclins that bind, activate and provide substrate specificity to their associated catalytic partners, the cyclin-dependent kinases (CDKs) 1-4. Cell cycle progression can be divided into four phases: gap 1 (G1), DNA synthesis (S), gap 2 (G2) and mitosis (M). Depending on the mitogenic environment, cells traversing G1 phase either activate a program that will result in cell division, or they enter a quiescent G0 state 1-4 (Fig. 1a). At the molecular level, stimulation of cells with growthpromoting factors results in upregulation of the D-type cyclins (D1, D2 and D3), which activate the cyclin-dependent kinase 4 (CDK4) and CDK6 1-5. In a classical cell cycle model, cyclin D-CDK4/6 complexes, together with E-type cyclins (E1 and E2) and their associated kinases (primarily CDK2, but also CDK1 and CDK3) phosphorylate and functionally inactivate the retinoblastoma protein RB1, and pRB1-related RBL1 and RBL2 proteins 1-4. This leads to the activation or de-repression of E2F transcription factors, which then transactivate genes required for the entry and progression of cells into S phase 1-4,6,7. This model has been questioned by the demonstration that throughout most of G1 phase, RB1 exists in a mono-phosphosphorylated state, and becomes fully phosphorylated by cyclin E-CDK2 at the end of G1 phase 8. In addition to RB1 phosphorylation, inactivation of Cdh1, a substrate recognition subunit of the anaphase promoting complex (APC/C), contributes to an Correspondence should be addressed to: P.S. Competing interests PS has been a consultant at Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals and Exo Therapeutics; his laboratory receives research funding from Novartis. WM is currently an employee of Cedilla Therapeutics.