Video: Cell cycle

Ah! A paper cut. So small, yet so painful. But before you know it, it’s healed like it never happened. How does our skin repair itself so well? Where do the new skin cells come from? They get replaced by division of existing skin cells. This is part of a bigger process where cells grow and reproduce. And in this tutorial, we’ll be learning all about the cell cycle.

The cell cycle is a sequence of events involving cell growth and reproduction. The end goal is for the cell to divide into two identical daughter cells. Each cell cycle has two major phases. The phase where the cell divides, known as the M phase. And the phase where it prepares for that division, known as interphase. Let’s start with interphase.

Interphase is the preparation phase. Just like with a race, where the preparation and training take longer than the race itself, interphase is longer than the M phase. It is further subdivided into the G1, S and G2 phases. The G1 and G2 phases are sometimes called gap phases. However, this term is not actually correct, as a lot of growth and metabolic activity takes place during these phases. The cell is actually quite busy during this time, making proteins and enzymes necessary to replicate its DNA and organelles. All the work that takes place during G1 is in preparation for the next phase of the cycle, where DNA replicates. In the S phase, DNA is replicated to ensure that each daughter cell gets an equal amount of DNA when the cell divides. They need to be identical to the parent cell.

The process of DNA replication starts when the enzyme DNA helicase unwinds the two strands. DNA replication is tricky as the enzyme involved, DNA polymerase, needs to attach the nucleotides to other nucleotides to form new DNA strands. That’s why the RNA primase synthesizes a short, temporary stretch of RNA. Now DNA polymerase can come in and start making DNA.

Recall that DNA strands are antiparallel. One is in the five prime to three prime direction and the other is three prime to five prime. DNA polymerase can only travel one way, synthesizing DNA in the five prime to three prime direction. Thus it synthesizes one strand easily, and that’s the leading strand.

But what about the other strand? This is where it gets messy because DNA polymerase cannot travel backwards. Thus RNA primase has to synthesize multiple RNA primers as the strands unwind, and the DNA polymerase synthesizes one section of DNA at a time. This strand, formed in fragments, is known as the lagging strand.

Exonuclease enzymes remove the RNA primers and another DNA polymerase replaces the RNA sections with DNA. Finally a DNA ligase seals them together. And just like that, we went from one DNA molecule to two. This process is semiconservative, as each DNA molecule retains one strand from the original.

Now that the cell’s DNA has been replicated, it enters the G2 phase where it continues to grow in preparation for cell division. Thus by the end of the G2 phase the cell has grown, has duplicated centrosomes, has an intact nuclear envelope and nucleolus, with fine thread-like chromatin distributed throughout the nucleus containing the duplicated DNA.

Now the cell is ready to divide in the M phase. The M phase includes mitosis and cytokinesis. Mitosis refers specifically to nuclear division, while cytokinesis refers to cytoplasmic division. Let’s start with mitosis. It includes prophase, prometaphase, metaphase, anaphase and telophase.

Prophase is the first stage of mitosis, where the chromatin condenses to form chromosomes. They become denser and thicker and thus the two sister chromatids, each representing a copy of DNA, become clearly visible. They are held together at a constriction, known as the centromere. The duplicated centrosomes start moving apart, forming microtubules between each other.

During prometaphase, also known as “late prophase”, the nucleolus disappears and the nuclear envelope breaks down. The centrosomes move towards opposite poles of the cell and the spindles extending from them invade the nucleus and grab onto the chromatids. This attachment occurs at specialized regions of the chromosomes known as kinetochores. There’s one on each side, such that one spindle from each centrosome attaches to a chromatid on either side. This results in a tug of war between the two sides, as the cell enters metaphase, where eventually the chromosomes line up along the equator of the cell. This imaginary plane where the chromosomes arrange themselves is known as the metaphase plate. The spindles that attach to the kinetochores are known as kinetochore spindles. There are non-kinetochore spindles which do not attach to chromatids. These overlap at the center of the cell with their partner from the opposite side.

Once all the chromatids are attached to spindles, the cell proceeds to anaphase. The kinetochore spindles shorten separating the chromatids at the centromere, such that one from each pair moves towards the opposite pole of the cell. The non-kinetochore spindles assist with movement of the chromatids towards the poles.

Finally the cell enters telophase, where the nuclear envelope reforms, nucleolus reappears and chromosomes decondense forming threadlike chromatin again. Telophase overlaps with cytokinesis. Towards the end of mitosis, a cleavage furrow forms between the two cells at the equatorial region. Created by cytoskeletal actin filaments along with myosin proteins, this furrow clinches the cell - like pulling a drawstring - splitting the cytoplasm and thus creating two identical daughter cells, each with their own set of organelles. Very importantly - the two cells have the same amount of DNA as the parent cell.

To ensure every step of this cycle occurs smoothly the cell cycle is tightly regulated. The cell cycle can be regulated by factors outside or inside the cell. Let’s first look at internal factors.

The major internal factors that ensure the cycle progresses from one phase to the next are proteins known as cyclins, and enzymes known as kinases, which phosphorylate the proteins and activate them. They are known as cyclin-dependent kinases. The cyclin-CDK complexes determine whether the cells can progress to the next stage.

Quality control occurs at multiple checkpoints during the cycle. Here the cell checks important things such as whether the environment is suitable for division, if there are enough nutrients, if DNA replication took place correctly and if the chromosomes are aligned properly before they separate.

Issues with any of these points can have catastrophic consequences. Imagine a cell where there was an issue with DNA replication, resulting in a DNA mutation. If cell division isn’t stopped, mutations can propagate to the daughter cells and then to the next set of daughter cells. A potential consequence of these kinds of mutations is cancer. How can the cell prevent this from happening?

When cell DNA is damaged, the cell cycle can be arrested so that DNA can be repaired. This is triggered by factors such as tumor suppressor proteins, an important one being p53, which holds the title of “guardian of the genome”. If the damage is irreparable, the cell can undergo a form of programmed cell death known as apoptosis.

Now that we’ve learned about factors inside the cell, what about those outside?

External factors regulating the cell cycle include proteins such as growth factors. These factors are produced by other cells and can stimulate cell proliferation, pushing a cell to enter the cell cycle and divide. Why would cells need this stimulation?

Some cells exit the cycle and enter a resting stage known as the G0 phase. These are healthy cells that either do not divide again, such as most skeletal muscle and nerve cells. They generally cannot be convinced to re-enter the cycle. Or, they are cells that rest temporarily, such as those of the liver. When they receive external signals, these cells can and do reenter the cycle to start dividing again. Some cells, such as stem cells of the skin, can restart the cycle immediately when stimulated, effectively skipping G0.

This is why when a skin wound heals, the quick division makes it seem like painful incidents such as paper cuts never even happened.

And that concludes this tutorial on the cell cycle. Use our spaced repetition quizzes to cycle through what you’ve learned only on Kenhub!