Cell Cycle 101: Cell Cycle Regulation and Its Engines
Foreword
Have you ever questioned how a wound heals? How does an embryo become a baby? How does a cancerous tumor grow? At the heart of these questions lies cell replication and division. The remarkable ability of a cell to grow and divide into two identical daughter cells underpins the success of life. This is, however, only conceivable because eukaryotic cells (that is, with nuclei) go through the cell cycle, a set of well-defined and tightly synchronized events. This process is divided in two main stages: the interphase, whereby a cell grows; and the mitotic phase, by which cells replicate (mitosis) and divide (cytokinesis). During this process deoxyribonucleic acid (DNA), also recognized as the "molecule of life," is accurately replicated and faithfully distributed to newly generated daughter cells. DNA is the molecule that carries and conveys hereditary material or genetic information from parents to offspring, thus holding all the information needed to construct and sustain an organism. The cell cycle thus functions as the master regulator of tissue growth, development and proliferation. It also ensures that old cells are removed in a timely manner as we age and replaced by new cells that proliferate in a tightly controlled fashion. This keeps the total number of viable cells constant, which is essential for life as we know it.
The Cell Cycle 101 series attempts to elucidate the most important aspects of the cell cycle: from its history and discovery to the underlying mechanisms that control cell division. This series aims to explore the intricacies of cell cycle control in development and the consequences of its failure in disease.
Therefore, this series is divided into the following chapters:
4. Cell Cycle 101: Cell Cycle Regulation and Its Engines
Cell Cycle 101: Cell Cycle Regulation and Its Engines
Sequential and temporally controlled transitions occur when cells move from one phase of the cell cycle to the next. This comprises several checkpoints that monitor external and internal cues and verify that a cell is fully prepared to enter the next phase, as outlined in the previous chapter of this series. Yet, such signals must have an effect on the activity of cell cycle regulators, which are molecules capable of actively supporting or preventing critical biological processes like DNA replication or chromosome segregation (Crosby, 2007). Prior to the advent of modern genomics in the 1990s, cell cycle control was investigated using two main model systems: genetic modification in yeasts and biochemical investigation of early embryonic cell division in frog eggs (Uzbekov & Prigent, 2022). These different technical approaches culminated in two seemingly divergent models: the domino model in yeasts and the clock model in frog eggs. Yet, recently discovered proteins that have important functions across both models enabled the reconciliation of the two (Murray & Kirschner, 1989; Padgett & Santos, 2020). This parallelism illustrates critical features of cell cycle regulation that have been conserved in all eukaryotic organisms throughout evolution. At the heart of cell cycle regulation lie periodic waves of activity of dimeric (with two subunits) complexes, which function as the driving force behind cell cycle progression (Goodsell, 2019). These complexes entail a cyclin-dependent kinase (CDK), i.e., a protein which acts as a biological catalyst thereby accelerating chemical reactions (catalytic subunit) and a set of other proteins known as cyclins (regulatory subunits). Both function as master regulators of the cell cycle progression which, along with cell cycle checkpoints, guarantee that cell cycle events occur in the correct order and that the completion of one phase triggers the onset of the next one (Lim & Kaldis, 2013; Shehata, 2022).
The Engine and Its Gears
Cyclins, one of the most fundamental regulators of the cell cycle, are a group of proteins that control cell cycle progression by activating or inactivating other target molecules within a cell (Lents & Baldassare, 2016). Cyclins drive cell cycle events by working in concert with a family of enzymes called cyclin-dependent kinases (CDKs) (Lents & Baldassare, 2016; Noble & Endicott, 2001). While an isolated CDK is inactive, binding to a cyclin molecule activates it, rendering it a functional molecule hence allowing it to modify other target proteins. This is only possible because CDKs are kinases, which are enzymes that phosphorylate (attach phosphate groups to) specific target proteins (Malumbres, 2014). The attached phosphate group acts like a switch, making the target protein more or less active. When a cyclin binds to a CDK, it has two important effects: it activates the CDK as a kinase, but it also directs the CDK to a specific set of target proteins required for cell cycle progression at a specific stage (Malumbres & Barbacid, 2005; Shehata, 2022). This is only conceivable because each cyclin is associated with a particular cell cycle phase, transition, or set of phases and helps drive the events of that phase or period. There are four basic types of cyclins, each linked to a specific phase: G1-cyclin, G1/S-cyclin, S-cyclin and M-cyclin. Therefore, CDK1 and cyclin B1 regulate the G2/M transition. Departure from G1 was discovered to be predominantly controlled by cyclin D which binds CDK4 and CDK6. Ultimately, two additional cyclins (A and E) that work with CDK2 were discovered to be essential for the G1/S transition and entry into the S phase (Sanchez & Dynlacht, 2005).
As the name implies, cyclins activity is cyclic in nature, with each cyclin being present at low levels during the majority of the cycle, peaking only at the time when it is most needed (Hochegger et al., 2008; Lim & Kaldis, 2013). Consequently, as the cell moves to the next stage of the cell cycle, the cyclins that were active in the previous stage are degraded as they are no longer needed in the following phase. For instance, M cyclin peaks only at the G2/M transition to then promote the events of the M phase, such as nuclear envelope breakdown and chromosome condensation. One exception is G1 cyclins, in that they are needed for much of the cell cycle, including DNA replication and cell division, thereby exhibiting high expression levels throughout most of the cycle (Arand & Sage, 2017; Murray, 2004). By contrast, CDK levels stay steady throughout the cell cycle, yet its activity as well as target proteins vary; a consequence of variable levels of cyclins, which rise and fall as cells progress through the cycle (Hochegger et al., 2008). Besides requiring a cyclin partner, CDKs must also be phosphorylated, i.e., receive a phosphate group, in a particular site in order to activate, a role filled by CDK-activating kinases (CAK) (Liu & Kipreos, 2000). Additionally, CDK activity is also controlled by the phosphorylation of other sites by CDK inhibitors (CKIs), which serve as brakes to halt cell cycle progression under unfavorable conditions (Crosby, 2007). Close cooperation between this trio is necessary for ensuring orderly progression through the cell cycle. Cyclins and CDKs are highly evolutionary conserved and thus found in many different organisms, yet, the complexity and regulation of the system vary according to the species. While in yeast the cell cycle is governed by a single CDK; humans, by contrast, rely on several distinct CDKs which are activated at different stages of the cell cycle (Liu & Kipreos, 2000). Biochemical oscillations of CDK–cyclin activity are at the heart of cell progression through the various checkpoints in a temporally coordinated manner, in such a way that distinct cyclin-CDK combinations drive transition through different cell cycle phases or processes. Consequently, these regulators play an essential function in the control of cell growth and survival, hence being engaged in a variety of pathophysiological processes, such as development, tissue regeneration, or cancer.
Lessons from Yeast: The Domino Model
By virtue of their small size and genomes, rapid growth and ease of experimental manipulation, yeasts are incredibly useful organisms for genetic studies. As rapidly dividing unicellular organisms, yeast cells require efficient growth-regulating mechanisms, yet these are considerably simpler than those required for a more complex multicellular lifestyle (Tullio, 2022). Genetic research into cell cycle control primarily relies on two yeast model organisms: Saccharomyces cerevisiae (S. cerevisiae), a budding yeast that divides asymmetrically into a larger mother cell and a small daughter cell, or bud; and Schizosaccharomyces pombe (S. pombe), a yeast that divides by fission, with the mother cell increasing in size and dividing into two equal-sized daughter cells after mitosis (Botstein & Fink, 2011). Temperature-sensitive mutants in budding and fission yeasts have paved the way for researchers to understand how the eukaryotic cell cycle works and how it is regulated. These mutants are defined as those that cannot form colonies at high temperatures (35-37 °C) but grow normally or nearly so at normal temperatures (typically 25 °C for yeast cells) (Ben-Aroya et al., 2010; Li et al., 2011). Thus, in a temperature-sensitive mutant, the altered gene is rendered inactive only under restrictive temperatures, and therefore the associated phenotype may only be visible under such conditions. This allows the determination of the function of a specific gene in a specific timeframe of the cell cycle through temperature control, that is upon shifting the cells to a non-permissive temperature, providing a powerful approach for analyzing gene function (Li et al., 2011).
Lee Hartwell's seminal publications in the 1970s detailing the first mutations in temperature-sensitive S. cerevisae mutants served as a starting point for the discovery of cell cycle regulation as we know it today (L. H. Hartwell, 1967). Arrested at various stages of the cell cycle, these mutants were therefore unable to complete the cell cycle, revealing which genes were required for proper cell division. These genes have been called cell division cycle (cdc) genes (Leland H. Hartwell, 1971, 1973). By observing that cell cycle commencement in S. cerevisiae coincides with the appearance of a bud on the surface of the mother cell (which then increases in size during the cell cycle), Hartwell was able to isolate and identify 400 cell cycle-related mutants. To do this, Hartwell assessed the presence and size of the bud in mutants after transition to restrictive temperatures. Motivated by Hartwell's findings, Paul Nurse discovered cdc mutants in the fission yeast S.pombe, which has been shown to share most of the cell cycle regulatory network and genes, albeit its evolutionary distance (Nasmyth & Nurse, 1981; Nurse et al., 1976). However, fission yeast does not divide by budding, so there are no visible buds. Nurse drew on previous findings by Kohiyama (Kohiyama et al., 1963) to identify cdc genes in fission yeast. Kohiyama noticed that E. coli mutants that had arrested the cell cycle continued to grow and lengthen abnormally without dividing. This was the strategy Nurse used when studying fission yeast, identifying cdc genes in temperature-sensitive mutants that were lengthened due to an inability to enter mitosis and divide properly.
These preliminary studies established 30 cdc genes necessary for the successful completion of the cell cycle (Nasmyth & Nurse, 1981; Nurse et al., 1976). Given that these two species last shared a common ancestor more than a billion years ago, Nurses' findings implied that these genes were highly conserved throughout evolution and were likely similar in other organisms (Sipiczki, 2000). This was demonstrated for the cdc2 gene, shown by Nurse to be the master cell cycle regulator in fission yeast and found to be functionally identical to one of the genes identified by Hartwell in the budding yeast, which he termed cdc28. In 1987, Nurse demonstrated the universality of this gene by isolating the corresponding human version and showing that when inserted into S. pombe, the yeast continued to function, a milestone in cell cycle history (Lee & Nurse, 1987).
The advent of genetic manipulation in mice has fuelled the study of cell cycle regulation in more complex species. Research has shown that the mammalian cell cycle has evolved to include additional CDKs compared to yeast, such that the functions of a single CDK in yeast are now shared among multiple mammalian CDKs (Sanchez & Dynlacht, 2005). Although theoretically similar to the yeast system, mammalian cells change both CDKs and cyclins (rather than simply the cyclin) at each cell cycle stage in order to guarantee sequential and orderly progression throughout the cycle. This increased CDK diversity is believed to be the result of a growing demand for more sophisticated control over different cell types as species have evolved from unicellular to complex multicellular organisms (Malumbres & Barbacid, 2009). These findings demonstrate how a single gene that is necessary for the commencement or completion of a particular cell cycle phase ultimately precludes the cell from moving to subsequent phases, ultimately halting cell cycle completion. This emphasizes both the interdependence of cell cycle stages—that is, the dependence of the beginning of each phase on the orderly completion of all preceding phases—as well as the sequential ordering of cell cycle events (Leland H. Hartwell & Weinert, 1989). This paradigm culminated in the ‘domino-like’ model of cell cycle control. According to the domino model, the G1/S transition to initiate DNA replication, G2/M to enter mitosis, and metaphase/anaphase to exit mitosis must take place at a particular timing and in a predefined order. This implies that progression through the distinct cell cycle phases must be unidirectional (Leland H. Hartwell & Weinert, 1989; Murray & Kirschner, 1989).
Clock-Like Division: Insights from Frog Eggs
Embryonic cell cycles, particularly those of the well-studied frog Xenopus laevis, have unique features (Murray & Kirschner, 1989; Newport & Kirschner, 1984). Frog zygotes are unusually large cells (1.2mm in diameter) that divide every 30 minutes (Pomerening, 2013). Its size allows for enucleation (nuclear removal) and nuclear transplantation, enabling it to disentangle the functions of the nucleus and the cytoplasm. Unlike somatic cells (non-reproductive), embryonic cell cycles lack a growth phase and cannot be halted even if there is DNA damage (Hyka-Nouspikel et al., 2012; Padgett & Santos, 2020). This allows for exceptionally rapid cell cycle rates, and yet synchrony is maintained during these primitive cell division cycles (Gerhart, 1980; Hara et al., 1980; Newport & Kirschner, 1984). Biochemical fluctuations of CDK-cyclin activity are at the foundation of early embryonic divisions, allowing these cells to function as oscillators, rapidly alternating between genome replication (in S-phase) and chromosomal segregation, followed by cleavage of daughter cells (M-phase) (Lohka & Masui, 1983; Padgett & Santos, 2020). Kirschner's now-famous “bouncing frog-egg” experiment revealed a fundamentally different mode of cell cycle regulation than that of the yeast domino model, today known as the clock model (Murray & Kirschner, 1989). Frog eggs are naturally arrested cells that require fertilization to be cleaved. However, cell division in frog eggs can be artificially induced in the laboratory, via biochemical techniques such as pricking. Hara and Kirschner observed that enucleated Xenopus eggs which were stimulated to exit cell cycle arrest displayed synchronized and clock-like oscillations, known as “surface activation waves” (Hara et al., 1980; Murray & Kirschner, 1989; Newport & Kirschner, 1984). These movements, seen from the side, made the eggs bounce up and down.
Follow-up experiments consisting of dividing a Xenopus egg by constriction, with one half holding the nucleus and the other half containing only the cytoplasm, demonstrated that the nucleus is not essential for the propagation of these periodic waves. These findings show the existence of a biological clock in the cytoplasm of vertebrate eggs that acts independently of the nucleus and that is critical for cell cycle regulation, namely in driving mitosis. The apparent mitotic driving force underlying these oscillations was later identified as the M-phase/maturation promoting factor (MPF), whose activity is greatest during the commencement of mitosis, peaking every 30 minutes in the cleaving Xenopus embryo (Dunphy et al., 1988; Jevitt & Susannah, 2022; Kimelman et al., 1987). MPF resembles a cytoplasmic oscillator or clock, which guarantees a synchronized embryonic cell cycle and hence operates as a cell cycle engine (Jevitt & Susannah, 2022; Masui & Markert, 1971), timing events like DNA replication and mitotic entrance.
Conclusions
The intricacies of cell cycle regulation, as we know it today, stem from two parallel lines of research. While geneticists sought to understand the cell cycle by studying mutations that halted cell cycle progression in yeast; embryologists and physiologists focused on the biochemical study of early embryonic cell division in frog eggs. These contrasting approaches led to the emergence of two divergent models that over time have proven to be more complementary than exclusive. The genetic manipulation of yeast cdc mutants by Hartwell and Nurse enabled the establishment of the linear sequence of cell cycle events, emphasizing the interdependence of cell cycle stages. Since the execution of later events depends on the completion of the preceding ones, this view has come to be known as the domino model. The rapid contractions of an enucleated Xenopus egg, on the other hand, revealed the existence of a cytoplasmic timer regulating mitotic entry, a concept referred to by Kirschner as a clock model. While the discrepancies appeared to overshadow the similarities at first, later deconstruction of key molecules involved in cell cycle control revealed functional links between the yeast and frog egg regulatory systems. The discovery of MPF, the cytoplasmic component driving mitosis in Xenopus eggs, subsequently found to be the mammalian cdc2 homologue, was the last piece that brought two opposing perspectives together.
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