13. The Cell Cycle (1,046;10/14;Ready)

Every second, your body replaces millions of cells--roughly 330 billion every day. Most are blood cells, but cells are also continually replaced in the lining of the gut, the skin, hair follicles, and other tissues.

Producing these replacements requires an extraordinary number of cell divisions. Before a human cell can divide, though, it must duplicate more than six billion base pairs of DNA, organize the resulting copies, compact them into separable chromosomes, and distribute one complete set to each daughter cell. It must also divide thousands of other cellular components between the two cells.

Not everything will be divided with equal precision. Each daughter cell must receive exactly one copy of every chromosome, but proteins, membranes, and organelles are divvied up more approximately. The daughter cells can correct small imbalances afterward. The genome, however, leaves little room for error.

The rate of cell division varies dramatically among cell types. As mentioned, cells in bone marrow, intestinal lining, skin, and hair follicles divide continually to replace those that are lost. Other cells, such as neurons, divide rarely or have permanently stopped dividing.

Cell division also built your body in the first place. I always marvel over the simple fact that every cell in an adult can trace its lineage back to one single fertilized egg. Only about forty rounds of perfect doubling would turn that one cell into more than a trillion, although actual development is far more complicated.

All this growth and renewal depends on a recurring program called the cell cycle. The cell cycle consists of a series of commitments on the part of the dividing cell that ultimately results in two cells. During the cell cycle, there are also multiple molecular checkpoints that can delay next steps if conditions are not right.

The cell cycle

The cell cycle coordinates cell growth, genome replication, and cell division. In many actively dividing human cells, it takes roughly 24 hours, although the timing varies. It consists of four phases:

• G1 (gap 1): the cell grows and decides whether to divide

• S (synthesis): the cell duplicates its DNA

• G2 (gap 2): the cell completes its preparations for division

• M (mitotic phase): the cell separates its chromosomes and divides

The cell cycle.

S and M phases produce the cycle’s two defining outcomes: a duplicated genome and two daughter cells, respectively. They are also among the riskiest operations a cell performs. An error in copying or distributing the genome can be passed to every descendant of that cell.

Cells that are not preparing to divide and are instead carrying out their usual functions are said to be in G0--pronounced “G-zero.” Most nucleated cells in an adult body are in G0 rather than actively progressing through the cell cycle. Some can reenter the cycle at G1 when stimulated by growth signals; others, including most mature neurons, have withdrawn permanently.

For cells that do divide, during the first phase, G1, they grow and assemble the machinery required for DNA replication. Near the end of G1 is the G1/S checkpoint where the cell assesses its size, the availability of nutrients and growth signals, and the integrity of its DNA. At this and other cell cycle checkpoints, unresolved problems generate molecular signals that block the next transition. But if conditions in G1 are favorable, the cell commits to entering S phase and synthesizing a new genome.

During S phase, as the cell is replicating its genome, an ongoing surveillance system called the intra-S checkpoint monitors DNA damage and stalled replication forks. If problems arise, the cell can slow replication, stabilize the forks, and provide time for repair.

In G2, the cell is completing its preparations for division. Near its end is the G2/M checkpoint, where the cell ensures that DNA replication is complete and that no serious DNA damage remains before entering M phase, or mitosis.

It is during mitosis that the now-duplicated chromosomes prepare to separate. The spindle-assembly checkpoint delays separation if any chromosome remains unattached to the molecular apparatus that will pull the copies apart. Even one unattached chromosome can generate a “wait” signal that delays all of them.

Once this checkpoint is satisfied, the chromosomes move apart. And then as mitosis nears completion, cytokinesis pinches the cell in two, producing two daughter cells.

Regulating the cell cycle

During the cell cycle, successive waves of molecular activity drive the cycle forward. At the center of these waves are two families of proteins: cyclins and cyclin-dependent kinases, or CDKs. CDKs, activated by cyclins, transfer phosphate groups from ATP to precise locations on other proteins. Adding a phosphate can change a protein’s shape, activity, location, or interactions.

CDKs are inactive unless joined by the right cyclin. Cyclins therefore act like a succession of specialized keys, activating particular CDKs at different points in the cycle. The resulting cyclin–CDK pairs go on to phosphorylate (i.e., attach a phosphate group to) many target proteins which sets whole collections of cellular events in motion.

During the celll cycle, cyclin levels rise and fall in overlapping waves. To begin, cyclin D activates CDK4 and CDK6 during G1. Then cyclin E–CDK2 helps commit the cell to DNA replication in S phase and cyclin A–CDK2 helps drive S phase. Later, cyclin A–CDK1 helps prepare the cell for mitosis, while cyclin B–CDK1 triggers its entry. Destruction of cyclins A and B allows mitosis to end.

Thus, the cell cycle is like a self-propelled molecular relay. Each wave completes one stage and creates the conditions for the next, while checkpoint signals can interrupt the handoff. No single molecule oversees the process; order emerges because each event changes the conditions faced by everything that follows.

Failures in the cell cycle control system are a defining feature of cancer. Mutations can disable the molecular brakes, jam the accelerators, or allow damaged DNA to pass through a checkpoint. The same machinery that normally builds and renews the body can then drive uncontrolled growth.

Yet in healthy cells, the cycle unfolds with astonishing reliability. More than six billion base pairs are duplicated, organized, and divided between two new cells due to countless local interactions that collectively produce an orderly sequence.

Having situated S phase in the context of the cell cycle, in the next chapter we'll kick off our focus on genome replication.