An introduction to the cell cycle
By Johannes Buheitel, PhD
“Omnis cellula e cellula”. We all heard or read this sentence probably sometime during college or grad school and no, it’s not NYU’s university motto. This short Latin phrase, popularized by the German physician/biologist Rudolf Virchow, states a simple fact, which, however, represents a fundamental truth of biology: “All cells come from cells”. It’s so fundamental that we often take it for granted that the basis for all of those really interesting little pathways and mechanisms that we study is life itself; and, moreover, that life is not simply “created” from thin air but can actually only derive from other life. Macroscopically, you (and Elton John) might call this “the circle of life” but microscopically, we’re talking about nothing less than the cell cycle. But what is the cell cycle exactly? What has to happen when and how does the cell maintain this order of events?
The cell cycle’s main purpose is to generate two identical daughter cells from one mother cell by first, duplicating all its genetic content in order to get two copies of each chromosome (DNA replication), and then carefully distributing those two copies into the newly forming daughter cells (mitosis and cytokinesis). These two major chromosomal events take place during S phase (DNA replication) and M phase (mitosis), which during consecutive cycles alternate, separated by two “gap” phases (G1 between M and S phase and G2 between S and M phase; FYI: everything outside M phase is also sometimes also called interphase). It goes without saying that the temporal order of events, G1 to S to G2 to M phase, must be maintained at all times; just imagine trying to divide without previously having replicated your DNA! And not only the order is important, but each phase must also be given enough time to faithfully fulfill its purpose. How is this achieved?
If you want to boil it down, there are two main principles that drive the cell cycle: timely expression and degradation of key proteins and irreversible switch-like transitions, called checkpoints. So let’s try and get an overview over each of these principles.
In the early eighties, a scientist called Tim Hunt performed a series of experiments, unknowing that these will turn into a body of work, which will ultimately win him a Nobel prize. For these experiments, he radioactively labeled proteins in sea urchin embryos (yes, you read correctly!) and stumbled across one that exhibited an interesting pattern of abundance over time in that it appeared and vanished in a fashion that was not only cyclic but also seemed to be in sync with the embryos’ division cycles. Dr. Hunt had just found the first member of a protein family, which later turned out to be one of the main drivers of the cell cycle: the cyclins. What do cyclins do? Cyclins are co-activators of cyclin-dependent kinases or Cdks, whose job it is to phosphorylate certain target proteins in order to regulate their function in a cell cycle-dependent fashion. Since Cdks are pretty much around all the time, they need the cyclins to tell them, when to be active and when not to be. There are a variety of different Cdks, which interact very specifically with various cyclins. For example, cyclin D interacts with Cdk4 and 6 to drive the transition from G1 to S phase, while a complex between cyclin B and Cdk1 is required for mitotic entry. This system allows for enough complexity to explain how the proper length of each phase is assured (slow accumulation of a specific cyclin until the respective Cdk can be fully activated), but also how the correct order of events is maintained; because it turns out that the expression of, say, the cyclin assigned to start replication (cyclin E) is dependent on the activity of the Cdk/cyclin complex of the previous phase (in this example: Cdk4/6-cyclin D) via phosphorylation-dependent regulation of transcription factors.
The second principle I was talking about, are checkpoints. A checkpoint is a way for the cell to take a short breath and check if things are running smoothly so far, and if they are not, to halt the cell cycle in order to give itself some time to either resolve the issue or, if that’s not working out, throw in the towel (i.e. apoptosis). Researchers describe more and more checkpoint-like pathways that react to different stimuli all over the cell cycle, but canonically, we distinguish three main ones: the restriction checkpoint at the G1 to S phase transition, the DNA damage checkpoint at the G2 to M phase transition and the spindle assembly checkpoint (SAC) during mitosis at the transition from metaphase to anaphase. What do these checkpoints look for, or in more technical words, what requirements have to be met in order for a checkpoint to become satisfied? The restriction checkpoint integrates a variety of internal and external signals, but is ultimately satisfied by proper activation of S phase Cdk complexes (see above). The DNA damage checkpoint’s main function is to give the cell time to correct DNA damage, which naturally occurs during genome replication but can also be introduced chemically or by ionizing radiation. Therefore, it remains unsatisfied as long as the DNA damage kinases ATM and ATR are active. Finally, the SAC governs one of the most intricate processes of the cell cycle: the formation of the mitotic spindle including proper attachment of each and every chromosome to its microtubules. After a checkpoint becomes satisfied, one or more positive feedback loops spring into action and effectively jump re-start the cell cycle.
As one can imagine, all of these processes must be exquisitely controlled to ensure the mission’s overall success. In future posts, we will explore those mechanisms in more detail and will furthermore discuss, how a handful of biochemical fallacies can have the potential to turn this wonderful circle of life into a wicked cycle of death.