I have already mentioned the link between DNA damage and cancer/aging, and in summary, I highlighted that aging, like cancer, triggers DNA damage and that exposure to various stressors throughout our lives, both from within our body (such as free radicals) and from the environment (such as UV radiation and certain foods), can cause oxidative stress, which can lead to genomic instability and ultimately damage to our DNA.
Intertwined processes
This week I will focus on cellular senescence, another important factor in the link between cancer and aging. This process is usually triggered by oxidative stress, shortening of telomeres (the protective caps on our chromosomes) or activation of certain genes, resulting in cells stopping dividing. Two genes in particular that control the cell cycle play an important role in this process: TP53 (tumor protein 53) and CDKN2A (cyclin-dependent kinase inhibitor 2A).
TP53 (p53): Cellular Guardian and Anti-Cancer
The TP53 gene-encoded protein is responsible for sensing and responding to DNA damage in cells. In its simplest form, if serious DNA damage is detected in the cell before division, TP53 provides the necessary time to repair the damaged DNA. However, if the damage cannot be repaired, TP53 stops the cell cycle and initiates programmed cell death (apoptosis). This mechanism helps to control abnormal cells that could potentially become cancerous. We can therefore think of TP53 as a kind of “cellular guardian”. We can also say that it provides a defense mechanism against cancer development.
However, mutations (permanent changes in the inheritance sequence of a living being) or losses in the TP53 gene, which can also be triggered by cellular senescence processes, can lead to the inability of cells to respond effectively to damage and uncontrolled cell proliferation. As a result, “mutation accumulation” can occur in uncontrolled cells. Cells can therefore progress towards cancer.
CDKN2A: Cell Cycle Brake and Cancer Preventer
The protein encoded by the CDKN2A gene controls cell division by regulating the cell cycle. If a cell is prone to abnormally rapid division, CDKN2A steps in and pauses the cell cycle, preventing uncontrolled division. Mutations in this gene can result in unlimited cell division, one of the most important characteristics of cancer.
As a result, thanks to the cooperation of these two important proteins, cells are able to proliferate in a controlled and orderly manner. In this way, abnormal cell division and cancer development are prevented by protecting the health of the organism. However, mutations in the genes encoding these proteins can predispose to cancer development. As the organism ages, the likelihood of mutations in these genes increases and the risk of cancer increases.
In my next article, I will talk about the relationship of TP53, the cellular guardian, with another critical signaling pathway in the cell and what can be done for cellular cleansing.
References:
Wang Z, Strasser A, Kelly GL. Should mutant TP53 be targeted for cancer therapy? Cell Death Differ. 2022 May;29(5):911-920. doi: 10.1038/s41418-022-00962-9. Epub 2022 Mar 24. PMID: 35332311; PMCID: PMC9091235.
Mijit M, Caracciolo V, Melillo A, Amicarelli F, Giordano A. Role of p53 in the Regulation of Cellular Senescence. Biomolecules. 2020 Mar 8;10(3):420. doi: 10.3390/biom10030420. PMID: 32182711; PMCID: PMC7175209.
Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer. 2012 Apr 15;130(8):1715-25. doi: 10.1002/ijc.27316. Epub 2011 Dec 5. PMID: 22025288; PMCID: PMC3288293.
Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev. 2014 Jan 15;28(2):99-114. doi: 10.1101/gad.235184.113. PMID: 24449267; PMCID: PMC3909793.
