Cell Biology
After being introduced to some of the genes and proteins that can impact the likelihood of cancer formation, it’s important to understand how those mutant proteins actually cause cancerous growth. To understand this, it’s essential to understand the cell cycle.
Within the cell cycle, there are two broad states that a cell can be in; either interphase or mitosis. Cells generally exist in interphase; interphase is a broad state in which a cell moves from stability to preparing for division in mitosis. Interphase itself has distinct phases within it.
Interphase:
G1 Phase
The initial phase within interphase is called the G1 phase, or Gap 1 phase. In the G1 phase, the cell is acting normally; making molecules, breaking down molecules, importing and exporting. Sometimes, cells can enter a phase called G0 (or G naught) where the cell is in an inactive state in the sense that it is not actively in the process of trying to divide. During the G1 phase, there are certain biological conditions or checkpoints that need to be present in order to continue further into the cell cycle. This can cover things such as does the cell have enough cellular resources to support two cells, is it large enough to support two cells, is the environment ideal for cell division, and so on.
If these checkpoints are met, then the cell can freely move forward from the G1 phase into the S phase, or synthesis phase. However, it is not free to reverse backwards. Once a cell passes through this G1 checkpoint, it is irresistibly committed to cell division.
Cells that oftentimes replicate into cancerous masses are often able to pass the G1 checkpoint, even if they may not be prepared to do so. The proto-oncogene HER2 that translates into the transmembrane HER2 protein plays a role in allowing cells to replicate before they are prepared to do so. The HER2 protein will bind to the epidermal growth factor (as discussed in the prior module), and this will set off chain reactions that help a cell to pass the G1 checkpoint. If there is an overabundance of HER2 protein, then there is a higher likelihood that the G1 checkpoint would be achieved, and the cell would move into the S phase.
S Phase
Within the S phase, DNA replication occurs with the assistance of an array of enzymes. Helicase will unzip the DNA strand, and single strand binding proteins will inhibit the DNA bases from reattaching to each other. During this stage, topoisomerase is further up the DNA double helix than helicase, and relieves the twisting pressure that is caused by Helicase by breaking and reforming bonds. Once the DNA is unraveled, primase lays down RNA primers on the DNA, and DNA polymerase III lays down DNA nucleotides from the origin of the primer. However, DNA polymerase III can only place DNA nucleotides in the 5’ to 3’ direction, creating a leading strand and a lagging strand. The leading strand is built forward continuously, but the lagging strand is built backwards in splices. DNA polymerase I is then able to replace the RNA primers with DNA nucleotides, and ligase reconnects the DNA strands together via ligation. Ultimately, this process occurs until the DNA is completely replicated, and there are two identical paired chromatids within the cell.
G2 Phase
After the S phase comes the G2 phase along with another checkpoint. At this stage, the cell can either continue preparing for mitosis or initiate apoptosis. At this checkpoint, the P53 protein and the BRCA proteins enter the scene. If DNA replication wasn’t accurate enough, P53 can initiate chemical reactions to repair it (in which BRCA proteins play a role in). If the DNA is too damaged to be fixed, P53 can signal for apoptosis.
So, if the TP53 gene itself has a mutation that translates into a P53 protein that’s function is compromised, then there’s an increased risk that errors in DNA replication won’t be detected and fixed. Even if they are detected, BRCA gene mutations could also compromise the function of BRCA proteins, again leading to the susceptibility of mutated DNA getting replicated.
Mitosis:
After interphase, the cell enters mitosis, where it divides into two daughter cells. There are four phases of mitosis. In Prophase, the centrosome replicates itself, and the two centrosome copies move to either side of the nucleus. The membrane of the nucleus breaks down, and the DNA (in the form of chromatids) begins to align in the center of the cell. Microtubules begin to form from the centrosomes, growing towards the center of the cell.
In metaphase, the microtubules that stretch from the centrosomes attach to either side of the chromatids, which are now aligned in the center of the cell (BRCA proteins also play a role during metaphase, to verify the chromosomes are aligned properly. This is called the M checkpoint; if the chromosomes aren’t aligned properly, then it could lead to chromosomal level mutations in anaphase).
In anaphase, motor proteins pull on the microtubules, and the chromatids are pulled apart from the centromere connection.
In telophase, a new nuclei starts to form in either half of the replicating cell. The cell begins to pinch in the middle, and cytokinesis results in two new cells.
Ranging from the stages of interphase, DNA replication, all the way up until mitosis, there are so many places something can go wrong. Tumor suppressor genes play an integral role in keeping these errors in check, but in the event that tumor suppressor genes themselves have mutations that inhibit their protein product from performing their essential functions, things could go awry.