Ars Biotech

p53, guardian of the genome🧬⚔️

p53 is the most known onco-suppressor, mutated in 40% of all solid tumour, it is “the guardian of the genome” because it’s activated by a lot of stress stimuli, including DNA damages, oxidative stress and hyperproliferative stimuli.
Missense mutations in the TP53, the gene which codifies for P53, are extremely widespread in human cancers and give rise to mutant p53 proteins that lose tumor suppressive activities, Cancer cells acquire selective advantages by retaining mutant forms of the protein, which radically subvert the nature of the p53 pathway by promoting invasion, metastasis and chemoresistance.
P53 can regulate the cell cycle, this is the most important function, he can incredibly rapidly block the cell cycle progression, either in G1-S and G2-M. Then it induces DNA repair mechanism stimulation, or better the production of transcription factors for DNA repair mechanism. Then in case there is nothing to do, it activates apoptosis.
But not only that, it also inhibits metabolic reprogramming, de-differentiation and invasion/metastasis capability.
In normal conditions, p53 translation levels in the cell would be sufficient to impair proliferation, eventually causing apoptosis, so it is expressed but is mostly bound to MDM2/4 complex, which keeps it inactive and ubiquitinated it, leading p53 to the proteasome degradation.
In case of DNA damages, as of other stimuli, (this activates ATM/ATR that phosphorylate MDM2 and MDM4 which are ubiquitinated releasing p53 from the complex, so that) p53 can go performing its activity.
Clearly, the variety of TP53 missense mutations produces distinct functional consequences, thus tumor vulnerabilities may differ based on the specific TP53 mutation, as well as on the tumor type. Much study is still required to define these aspects, moreover multi-mutant, multi-omic approaches could provide a clearer perspective on the range of mutp53 cancer-protecting activities, and their prevalence in different mutp53 variants and in different tumor contexts, helping to identify “core” mutp53 activities as ideal therapeutic targets.

Transposable Elements and their great evolutionary value 🧬🔬
Transposable elements are mobile genetic units, DNA sequences that can detach from their region of origin and fit into another part of the genome. The sequences of these elements are very heterogeneous, as are their transposition mechanisms. They have a great importance in biology because of their high mutagenic power, their insertion in another occupied gene’s or regulatory’s region of the genome can lead to more or less serious modifications, important or silent mutations, and diseases.
Transposable elements also play an important role in evolution, just think that in organisms such as corn, 60% of the genome consists of sequences belonging to transposable elements, thanks to which they have selected favorable mutations over time, leading to the evolution of the species. Many transposable elements, in model organisms such as drosophila, zebrafish, mouse, rat and in humans, after mobilizing within the DNA, they have undergone further mutations so as to no longer allow their movement, and remain a fixed part of the genome. The study of transposable elements is playing an increasingly important role in research, in order to diagnose and treat diseases not yet fully understood.

Pharmacogenomics🧬💊 is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup.
Many drugs that are currently available are “one size fits all,” but they don't work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions. Conditions that affect a person’s response to certain drugs include clopidogrel resistance, warfarin sensitivity, warfarin resistance, malignant hyperthermia, Stevens-Johnson syndrome/toxic epidermal necrolysis, and thiopurine S-methyltransferase deficiency.
The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.
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