This is in response to this question:
What role does DNA mismatch repair have in cancers? According to the slides this week, "Base-excision repair corrects the most common point mutation in humans, the deamination of methylcytosine to thymine." If this repair does not work, is there an abundant amount of genetic information and does that lead to cancer?
Your question really opens Pandora’s box. The deamination of cytosine into uracil or thymine is a hot topic in epigenetic research. Epigenetics is the theory that environment and experiences change the expression of genes, altering phenotypic expression in somatic and even germ cells. I found a helpful Harvard infographic that quickly explains epigenetics, which I thought might be helpful.
(What Is Epigenetics? The Answer to the Nature Vs. Nurture Debate, n.d.)
As you can see from the infographic, the original concept of DNA was that it was a blueprint that dictates phenotypic expressions. However, scientists now perceive that there are many regulators and modifiers of DNA that contribute to a diversity of gene expression. Additionally, these modifiers can be passed on from generation to generation.
Studies with rats have shown transgenerational modifications of gene expression based on early maternal-infant relations. For example, increased DNA methylation in the prefrontal cortex that causes depressive behavior is observed in rats abused by their mothers. This methylation is then passed on in subsequent generations and observed in male sperm and female/male somatic cells, along with observed depressive behaviors (Gudsnuk & Champagne, 2012). This methylation was not present in the DNA but is now present as an epigenetic marker influencing gene expression and is then passed on in germ cells. In other words, if a mother rat abuses her baby, it causes methylation in the cortex that causes depression in her baby and her baby’s babies. Epigenetics has a particular influence on the brain due to the plasticity of cerebral neurons.
And so, cytosine methylation into thymine (or uracil) is one of the key players in epigenetics. The transition mutation from cytosine to thymine has many implications when not corrected by base-excision repair, from increased variation in immunological defense to oncogenesis.
In terms of immunity, it is crucial to have antibodies that can recognize and defend against a large and ever-evolving diversity of pathogens. Deamination of cytosine is important for the hypermutation of somatic B cells that produce the necessary antibody diversity. Enzymes such as cytosine deaminases are crucial for an efficient immune system and shown to be lacking in humans with hyper-IgM immunodeficiency. Thus, the deamination of cytosine enables B cells to create the immunoglobin diversity necessary for efficient immunity. (Chahwan et al. 2012).
Counter to that, deamination mutations of cytosine are also implicated in many cancers. Studies have found that activation-induced cytidine deaminases (AID) cause early stop codons in tumor-suppressor genes in colorectal cancer (Morisawa et al. 2012). Further studies have shown that AID enzymes are present in overabundance in many organ cancers. Although different gene mutations are observed in different cancers, for example, the k-ras gene mutation in pancreatic cancers, and the c-myc gene in lung and lymphoma cancers, there may be a few underlying enzymes that induce different mutations, with AIDs being a key suspect. Additionally, AID expression increases due to cytokine stimulation, causing DNA alterations in tumor genes. Furthermore, AID-induced mice develop several types of organ cancers, from lung to lymphoma and more, due to cytosine deamination mutations (Morisawa et al. 2012).
In conclusion, cytosine deamination mutations cause both desirable and non-desirable changes in genetic expression in humans. Without AID enzymes, we would not have any defense against the countless pathogens that threaten us each day. However, cytosine mutations do cause mutations that enable tumors and cancers, specifically in the organs, and notably, that disable tumor-suppressing enzymes. It has even been suggested that our evolutionary adaptability would not be as robust without these epigenetic players that allow more immediate modification and interaction with our environment and experiences (Chahwan et al. 2012).
REFERENCES
Gudsnuk, K., & Champagne, F. A. (2012). Epigenetic Influence of Stress and the Social Environment. PubMed Central (PMC). Retrieved December 2, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021821/
What is Epigenetics? The Answer to the Nature vs. Nurture Debate. (n.d.). Center on the Developing Child at Harvard University. Retrieved December 2, 2022, from https://developingchild.harvard.edu/resources/what-is-epigenetics-and-how-does-it-relate-to-child-development/
Morisawa, T., Marusawa, H., Ueda, Y., Iwai, A., Okazaki, I., Honjo, T., & Chiba, T. (2008). Organ‐specific profiles of genetic changes in cancers caused by activation‐induced cytidine deaminase expression.International Journal of Cancer, 123(12), 2735-2740. https://doi.org/10.1002/ijc.23853
Chahwan, Richard, Sandeep N. Wontakal, and Sergio Roa. "Crosstalk between Genetic and Epigenetic Information through Cytosine Deamination."Trends in Genetics, vol. 26, no. 10, 2010, pp. 443-448.
