Interesting Insight into the Relationship Between TP53, Telomerase, and Telomere Length
Telomeres are repeated sequences at the end of chromosomes. A little of that length is lost with each cell division, and in this way telomere length acts as a countdown. Somatic cells become senescent or self-destruct when telomere length becomes too short, thanks in large part to the activity of TP53. This is a protective mechanism, removing cells that can become cancerous or otherwise harmful. Stem cells employ telomerase to maintain long telomeres, and supply a tissue with new daughter somatic cells to take the place of those lost to telomere shortening. Thus a tissue has some turnover of cells, allowing a degree of protection from the most harmful cell malfunctions. This study provides some insight into how these relationships play out in practice by sabotaging telomerase and p53, and observing the results.
Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 which leads to apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic aging. Similarly, zebrafish have restricted telomerase expression, and telomeres shorten to critical length during their lifespan.
Telomerase-deficient zebrafish (tert -/-) is a model of premature aging that anticipates aging phenotypes due to early telomere shortening. tert -/- zebrafish have impaired cell proliferation, accumulation of DNA damage markers and p53 response. These cellular defects lead to disruption of tissue homeostasis, resulting in premature infertility, gastrointestinal atrophy, sarcopenia, and kyphosis. Such consequences contribute to its premature death.
Here we reveal a genetic interdependence between tp53 and telomerase function. Mutation of tp53 abrogates premature aging of tert -/- zebrafish, prolonging male fertility and lifespan. However, it does not fully rescue healthspan. tp53mut tert -/- zebrafish retain high levels of inflammation and increased spontaneous cancer incidence. Conversely, loss of telomerase prolongs the lifespan of tp53mut single mutants. Lack of telomerase reduces two-fold the cancer incidence in double mutants and increases lifetime survival. Thus, we observe a reciprocal rescue of tp53mut and tert -/- that ameliorates lifespan but not spontaneous cancer incidence of tp53mut, likely due to higher levels of inflammation.
Off topic, but here is some new news on gene therapy delivery:
https://www.the-scientist.com/delivering-prime-editors-with-virus-like-particles-71710
"Unlike base editors or other CRISPR associated nucleases, prime editors rely on a Cas9-reverse transcriptase fusion protein, a nicking guide RNA, and a long prime editor guide RNA with a complex structure. Although these differences are advantageous in terms of on-target genome editing, they impede delivery through previously established methods.
The researchers engineered changes in the packaging and targeting components of their base editor eVLP system and modified linker molecules in the prime editor to improve editor assembly, particle packaging, and delivery efficiency. "Overall, we improved the efficiency of prime editing following delivery by these prime editor-engineered virus-like particles, these PE-eVLP, by an average of something like 65-fold," Liu said.
By using these improved particles in mice, the researchers achieved therapeutically relevant levels of prime editing locally through retinal injection and successfully partially restored visual function in a vision loss mouse model. "Those results are significant because they are, to our knowledge, the first time that a prime editor has been delivered as a protein-RNA complex in its final, most transient form, into an animal to rescue a genetic disorder," Liu added...
...The next step is to further improve the in vivo efficiency and tailor eVLP to target different tissues. Because eVLP include the envelope and structural proteins that help viral delivery methods home in on their destination,1 PE-eVLP may hold the key to future minimally invasive gene editing therapeutics that reach their target destinations. "I'm quite glad to see that they actually tested in vivo," said Lu. "If it is found that systemic delivery is also efficient, then there will be a lot of applications.""