Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases

Key Points

  • In addition to their well-established functions in driving cell proliferation, cell cycle proteins have several non-canonical roles.

  • D-type cyclins and their partner cyclin-dependent kinase 6 (CDK6) have direct, kinase-independent roles in augmenting or repressing gene expression.

  • In mammalian cells, cyclin D1 promotes, whereas cyclin A–CDK2 inhibits, DNA double-strand break (DSB) repair through homologous recombination. In yeast, CDK activity seems to dictate the choice of DSB repair between non-homologous end-joining and homologous recombination.

  • Cyclins are postulated to regulate apoptosis, autophagy and anoikis. Analyses of mice lacking D-type cyclins support pro-survival roles for these proteins in specific tissues.

  • Cyclin D1, CDK6 and the CDK inhibitor p27 (KIP1) can affect the actin cytoskeleton and cell migration through several mechanisms.

  • Cell cycle proteins have important roles in development and have important functions in the nervous system and in regulating the immune response.

  • Cyclins and CDKs are shown or postulated to regulate metabolism through different routes, including a direct role in controlling mitochondrial function.


The roles of cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), as core components of the machinery that drives cell cycle progression are well established. Increasing evidence indicates that mammalian cyclins and CDKs also carry out important functions in other cellular processes, such as transcription, DNA damage repair, control of cell death, differentiation, the immune response and metabolism. Some of these non-canonical functions are performed by cyclins or CDKs, independently of their respective cell cycle partners, suggesting that there was a substantial divergence in the functions of these proteins during evolution.

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Figure 1: Canonical roles of cyclins and cyclin-dependent kinases in the cell division cycle.
Figure 2: Cyclins and cyclin-dependent kinases in DNA double-strand break repair.
Figure 3: Regulation of cell death by interphase cyclins and cyclin-dependent kinases.
Figure 4: Roles of interphase cyclins and cyclin-dependent kinases in cell differentiation.
Figure 5: An integrated view of the roles of interphase cyclins and cyclin-dependent kinases (CDKs) in the control of cellular energy and physiological metabolism.


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This work was supported by US National Institutes of Health (NIH) grants R01 CA083688, R01 CA132740 and P01 CA080111 to P.S., and grants from the Spanish Ministry of Economy and Competitiveness (SAF2012-38215, SAF2014-57791-REDC and BFU2014-52125-REDT) and Comunidad de Madrid (S2010/BMD-2470) to M.M..

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Chromatin modifier

A protein complex that, through catalysing specific histone or DNA modifications, induces changes in chromatin to make it accessible (open) or inaccessible (closed) to the transcriptional machinery.


A post-mitotic state in which cells do not divide, although they may be induced to re-enter the cell cycle in response to specific stimuli.


Displacement loops formed in homologous recombination repair. Two strands of a homologous chromosome are separated for a stretch by an invading broken strand, forming a displaced single-stranded structure, the D-loop.


A form of programmed cell death characterized by the activation of specific proteases, termed caspases, which induce chromatin fragmentation and the degradation of various cellular components.


The degradation and recycling of cellular components and organelles by lysosomes.


A special form of programmed cell death that can be induced in anchorage-dependent cells by their detachment from the surrounding matrix.

Basic helix–loop–helix (bHLH) transcription factor

A protein that contains two helices separated by a loop (the HLH domain), which binds to DNA in a sequence-specific manner.

Asymmetric cell divisions

Special form of cell division in which the daughter cells have different fates, probably as a consequence of asymmetric distribution of cellular components during division.


Transplants from genetically non-identical individuals of the same species.

Exocyst complex

A highly conserved, octameric protein complex that regulates vesicle delivery to, and docking at, the cell surface.

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Hydbring, P., Malumbres, M. & Sicinski, P. Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat Rev Mol Cell Biol 17, 280–292 (2016).

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