13. Cell Division and the Cell Cycle (1,218) DONE

Despite the title of this chapter, most of the time, most of your cells are just doing their jobs. They're not dividing.

Nerve cells are transmitting electrochemical signals. Heart muscle cells are contracting rhythmically. Rod and cone cells in the retina are detecting the words you’re reading.

But it's also true that your body is constantly renewing itself. Every day it replaces about 300 billion cells (1). That’s an enormous number--but it still represents less than one percent of all your cells.

The importance and rate of cell division varies dramatically from one tissue to another. Some tissues are high-turnover. Their cells divide continuously. These include bone marrow, the lining of the gut, the surface of the skin, and hair follicles--tissues exposed to constant wear. Other cells divide rarely or not at all, including those I just mentioned.

And, of course, there's also a developmental dimension to cell division. During embryonic development, cells divide at an astonishing pace. By birth, the human body contains about one trillion cells, meaning at least that many cell divisions had to have occurred to build the body from a single fertilized egg (2). Even after birth, cells divide more frequently during infancy and childhood than in adulthood.

All of this growth, renewal, and repair depends on a single recurring process: the cell cycle.

The cell cycle

Put simply, the cell cycle exists to prepare for and execute genome replication and cell division. The entire process is in service of those two goals.

For many human cells the cycle takes roughly 24 hours, though the timing varies widely. Those 24 or so hours are divided into four phases in the following order: G1 (for "growth 1"), S ("synthesis"), G2 ("growth 2"), and M (mitosis).

Cells that aren't actively dividing but just doing their jobs are often described as being in G0 ("G zero"). G0 is not part of the cell cycle. But a cell in G0 can enter the cell cycle at G1 if growth signals from the surrounding tissue reach it.

Of the four phases of the actual cell cycle, the S phase and M phase are primary--they respectively deliver the two outputs of the cell cycle: replication and division. The other two phases, G1 and G2, are focused on preparing for S phase and confirming that the cell is ready to divide in M phase, respectively.

The "S" in S phase stands for "synthesis." During this roughly eight hour period the over three billion nucleotide genome is replicated, or copied.

The "M" in M phase stands for "mitosis." In this last phase the two genomes are partitioned into two new daughter cells.

There are several distinct and highly choreographed steps in M phase. We'll discuss these in the next chapter.

As mentioned, the G1 and G2 phases play critical but supporting roles.

During G1 the cell grows and assembles the machinery for DNA replication. At the end of G1 there is a cell cycle checkpoint; the G1/S checkpoint. At this checkpoint the cell determines whether it should commit to another round of division.

Following S phase, the cell enters G2 where it prepares for division, or M phase. To do so it produces additional organelles and other cellular components to fill the two daughter cells.

Another checkpoint occurs at the end of G2: the G2/M checkpoint. Here the cell checks that the DNA copied during S phase is complete and free of major damage and that the cell is ready for mitosis.

One more thing: After M phase there is a short phase called cytokinesis during which the cell pinches itself off completely at its midpoint to become the two new daughter cells.

After cytokinesis, the daughter cell enters G1. From there it may proceed through another round of the cell cycle or exit into G0, where it can carry out its specialized function(s) without dividing.

The cell cycle.

Regulating the cell cycle

At each phase of the cell cycle, new sets of genes are turned on and others turned off to accomplish the tasks of that phase.

This turning on and off the appropriate genes is spearheaded by members of two protein families that work as partners: the CDK (cyclin-dependent kinases) family of enzymes and the cyclin family of regulatory proteins.

A CDK is a type of enzyme called a kinase. Kinases grab an ATP molecule, remove its last phosphate, and then attach it to specific amino acids on a specific other protein or proteins. The placement of a phosphate by a CDK must be exact.

Generally speaking, kinase-attached phosphate groups play enormously important roles in the cell by changing protein behavior. In some cases, they identify, or flag, a protein as a target for an action by another protein. In other cases, the phosphate changes the conformation (shape) of the protein in order to activate it, deactivate it, or alter its function.

In other words, kinase-attached phosphate molecules are powerful switches with different purposes depending on the protein, where it is attached on that protein, and the cellular context.

Fundamentally, the cell cycle is driven by molecular partnerships between specific CDKs (which are kinases) and specific cyclins (which turn specific CDKs on and off).

Members of the CDK family are present in the nucleus all the time but remain inactive unless bound to a partner cyclin. CDKs are like machines wandering around waiting for the right key.

The expression of different cyclins is associated with different phases of the cell cycle. When a particular cyclin is expressed, it binds to a specific partner CDK and switches it on.

Being a kinase, the activated CDK then phosphorylates many other target proteins, triggering the events required for that phase of the cycle.

As one phase ends, its cyclin is destroyed and replaced by another, activating a new set of CDKs and moving the cell forward through the cycle.

One example will give you the flavor. The point here isn't to memorize cyclins and CDKs. It's to see how the cell keeps time--not with a clock, but with a carefully choreographed sequence of molecular activations.

Our example starts at the outset of G1 phase. Cyclin D in fact activates two partner CDKs: CDK4 and CDK6.

As the cell approaches the G1/S transition, cyclin E takes over, activating CDK2, which prepares the cell to copy its genome.

During S phase, cyclin A attaches to CDK2. This drives DNA replication. Later, in G2 and M phase, cyclin A and cyclin B activate CDK1. This carries the cell through mitosis and prepares it for cytokinesis.

The molecular details are unimportant. What is important is that the cyclins and CDKs involved differ from phase to phase. A series of different cyclins activates specific CDKs, and those CDKs drive the cell into the next phase.

The rollout of these cyclins must be precise because genome copying and cell division are two of the most dangerous things a cell does. Nearly every major failure of cell regulation, including many forms of cancer, traces back to mistakes made in replication and cell division.

In the next chapter, we turn to the fourth and final phase of the cll cycle--mitosis--where the duplicated chromosomes are carefully separated into two new cells.

(1) Scientific American, April 1, 2001, Our Bodies Replace Billions of Cells Every Day. https://www.scientificamerican.com/article/our-bodies-replace-billions-of-cells-every-day/?utm_source=chatgpt.com

(2) Bionumbers. Accessed 1-15-2025. https://bionumbers.hms.harvard.edu/bionumber.aspx?id=106413&ver=4&utm_source=chatgpt.com