Genetics, Cancer Cell Cycle Phases

Development

After mitosis, where the cells divide into 2 cells, they enter into the G1 phase, which is a place for resting and a checkpoint for complete genetic function before the cells can start replicating the DNA. This DNA replication occurs in the S phase of interphase and plays a crucial role in creating sister chromatids that can then separate later in the cycle.[2] 

After the S phase, the cell then again enters into a resting state known as G2 before continuing on to complete the cell cycle with mitosis. Cyclins and Cyclin-dependent kinases, also known as CDK's, are the 2 major proteins that play a role in regulating the cell cycle. These CDK's are created throughout the cell cycle and are used to phosphorylate downstream proteins essential for healthy cell growth.

On the other hand, cyclin is only created during specific times of the cell cycle and acts as a regulator. When either of these proteins is not functioning correctly, downstream elements are not properly functioning, such as the INK4a/ARF, which encodes for tumor suppressor proteins. However, tumors may grow, leading to cancer in these specific cells. 

Cellular

Overexpression of growth factors or a lack of suppressor proteins can lead to rapid uncontrolled cell division. As cells proliferate without regulation, tumors occur that can become deadly if not treated. Mitosis occurs infinitely. The cells never die in cancer, as cancer cells can utilize telomerase to add many telomeric sections to the ends of DNA during DNA replication, allowing the cells to live much longer than other somatic cells.[3] With this mechanism, cancer cells that usually die simply continue to divide. 

Biochemical

The main tumor suppressor gene that plays a crucial role in maintaining the cell cycle is p53, which is a transcription factor that plays a role in promoting growth arrest, DNA repair, and eventual apoptosis, or regulated death by the cell in damaging situations.[4]

One of the major DNA repair mechanisms is called Base excision repair, which is responsible for repairing mismatched bases throughout the entire cell cycle. Additionally, p53 also regulates the expression of many inhibitory proteins like p21, GADD45. These proteins can inhibit Cdc2, which is crucial for the cell to progress through mitosis or meiosis. The protein p21 also plays a role in allowing the cell to move on from through the S phase by regulating another protein CDK2, an important kinase in DNA synthesis. Without this suppressor gene, these proteins would not be inhibited correctly, leading to cancer in the cells.[5]

Cancer may also develop during the S phase if repair mechanisms like the ones discussed previously are not functional or if DNA polymerase loses its function to proofread mismatched pairs during the S phase, leading to unstable DNA and possible frameshift mutations result in nonfunctional regulator proteins.[6] 

Molecular Level

Once a mutation occurs or a mistake is not found, the cell will bypass the regulatory elements of the cell cycle leading to the progression of the mutation in all daughter cells, therefore showing the importance of halt mutated DNA before other cells form. Many chemotherapy drugs work to break strands of DNA to stop the replication of the cells once suppression has been bypassed; however, the drugs cannot distinguish between healthy DNA and harmful DNA, leading to the loss of many other cells, often associated with hair loss.[7]

Function

The cip/kip genes are also important regulatory genes as they inhibit kinase interaction in the cell leading to a halt in growth; when not functioning properly, these genes are not able to impede the growth of the cell, which could also lead to cancer.[8] Some many genes and proteins play crucial roles in the regulation of growth. An issue with any may lead to cancer; however, some proteins can sense these abnormalities and kill the cells before uncontrolled growth occurs.

Mechanism

Cancer may also arise from proto-oncogenic genes, which then mutate to become oncogenic or tumor-promoting genes. Mismatch repair during DNA synthesis in the cell cycle is an important mechanism that can halt continuation in the cycle for base pairs to be replaced before cell division. Proteins called Mismatch repair proteins are a group of 7 proteins that are important in repairing these mismatched sequences to prevent excessive growth. These proteins play a crucial role in DNA stabilization and can often lead to genetic instability, causing forms of the colon or rectal cancers that form on the right colon.

Additionally, cancer may also form from a lack of control during DNA sequence breaks. When DNA is damaged, and double-stranded breaks occur, most commonly from UV stress; ATM and ATR proteins can stop cell division until the strand is repaired. If the stand break occurs during the S phase of the cycle, several different proteins can find the homologous strand of the chromosome and use that as a template to reform the damaged DNA. If no similar strand is available, as in other phases of the DNA cycle, a nonhomologous repair can still occur but at the risk of forming a mutation from the newly repaired DNA. 

Clinical Significance

Cancer is an uncontrolled growth of cells leading to phenotypic expression in many forms, from mild to life-threatening. Cancer can develop in many ways, either from DNA damage, a mutation in the DNA or any product of that DNA, or by loss of function of the regulatory and repressor systems in the cycle.[9] 

In many cancer cells, there must be an issue on both alleles of a chromatid for cancer to occur. This is known as the two-hit hypothesis, and is the reason why cancer is often time heritable. Both alleles must be defective for cancer to occur; otherwise, the functioning allele will be favored, and cancer will be suppressed normally. Besides being passed down in genetics, environmental factors may also play a crucial role in developing cancer. Radical oxygens could lead to changes in the DNA and could lead to cancer if not corrected. Another common environmental factor that can damage DNA is UV light that radiates from the sun. This radiation can lead to the formation of thymidine dimers, which are normally fixed by nucleotide excision repair (NER); however, errors in this process can lead to misreading of the DNA and thus lead to cancer.[10] 

There are many reasons that cancer can occur; however, overall, cancer develops due to the inability of the cell to repress the growth once it has occurred. Overall, the cell cycle has many regulatory steps that are crucial to maintaining homeostasis inside of the cells during the replication of DNA and the division of cells. Mutation inside specific genes can lead to the loss of balance inside the cells, thus resulting in cancer growth. Cancer cells can also use specific telomerase to create long repeated sequences of telomeres that prevent the cell from going through apoptosis even after many repeats. The maintenance of all cell functions is important to prevent cancer growth; even small changes in certain genes can cause the over division of cells.