Insight on Cell Senescence:

             Cell senescence is a permanent, stable cell cycle arrest, where cells that have reached their division limit or have undergone stress, then exit the cell cycle and enter senesscence¹. This arrest state halts the division of the cell; however, the cell still maintains metabolic activities and secretes substances into the environment¹.  Senescent cells are associated with both protective and deleterious effects². A category important to mention is replicative senescence. Under replicative senescence, the cells have only a short telomere left, typically uncapped¹. The shortened telomere leads to DNA damage responses and triggers senescence². Accumulated findings support stress is the main way cells enter this phase instead of apoptosis¹. Majority of cells can reach this phase, and it can be understood as similar to the G0 phase of the cell cycle³. Don’t be misled though, the G0 phase is a resting state from the cell cycle and will return to division, often referred to as Quiescent ³. Cell senescence is the irreversible phase of G0³.

            The irreversibility of cell senescence is where concerns lie. While senescence has the ability to avoid malignant transformation of damaged cells, the onset of the state is known to contribute to pathologies like cancer, aging tissue, and inflammatory disease². The contribution to the pathologies lies in the secreted substances^1,2. These are known as pro-inflammatory senescence-associated secretory phenotype (SASP) that communicate with the surrounding cells and immune system².  SASP is responsible for both promoting and inhibiting tumor growth². The SASP’s ability to attract immune cells to senescence cells aids in their death, acting as a tumor suppression and preventation². However, SASP has also been found to induce tumor progression by releasing factors that stimulate angiogenesis, extracellular matrix remodeling, and epithelial-mesenchymal transition (EMT)². Further, chronic inflammation triggered by senescence can lead to systemic immunosuppression, possibly contributing to the development of cancer². This persistent inflammatory state not only affects immune function but may also accelerate tissue damage and aging-related degeneration as it communicates to the other cells². From this knowledge, the complexity of cell senescence is shown along with the uncertainties it holds.

A deeper look into Transcription:

            All processes have to begin somewhere and for normal transcription that is the promoter sequence⁴. A promoter sequence is the kickstart of the protein coding gene to be transcribed into RNA⁵. The promoter sequence holds an important power, depending on the length of the sequence on each DNA, the level of control for gene-expression differs⁴. Combination of promoter lengths and location on DNA, help create the variety and specific purposes of each promoter sequence⁴. Located just upstream of the coding sequence the increased surface area of longer promoter sequences allows more proteins to bind to the promoter sequence and the range of control can be quite dramatic⁴. Proteins binding to the promoter sequence is specific to eukaryotes, known as transcription factors and have specific chosen DNA for every binding process.⁴.

Interestingly, a phenomenon can occur, interfering with the normal transcription process⁵. From the above paragraph, we have learned that the promoter sequence is the beginning of a normal transcription process due to its specific location on the DNA⁵. This process is well regulated by the cells, but sometimes a look-alike sequence fools the process⁵. The phenomenon is called cryptic transcription and occurs when promoter sequence look-alikes exist on other locations within the DNA⁵. In mammalian studies, the arise of cryptic transcription is found to increase with cell age⁵.

In this process of another form of transcription can occur⁶. Cryptic Transcription occurs in senescent cells and normal cells and can have harmful consequences^5,6. RNA transcripts are produced from a short sequence that is located with individual genes⁶. However, how the harmful consequences of this process occurs, has been a question to scientist for years⁶.  What we do know is Cryptic transcription has been associated with spurious behavior, meaning any at chromatin region (gene sequence), RNA polymerase II can be recruited⁷.  This area is outside of the normal promoter sequence, and be called the cryptic promoter⁷.What makes this process cryptic is how the process functions within normal transcription, but creates an error-like expression in the gene when the cryptic promoter recruits the RNA polymerase⁷. Some studies have found Cryptic transcripts to be chromatin sensitive, allowing for a type of research to highlight the cryptic transcripts in the act, but many are still hard to detect⁷. A key difference between normal transcription and cryptic transcription is that normal transcription holds a strict process, while cryptic transcription sneaks into the process and changes the coding process unnoticeably until expressed^,6,7.

 The Misleading Zombie:

            One could say aging is like becoming a zombie, and in the paper “Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging⁸”, we will delve into the process of mammalian cells becoming a “zombie” with the topics we have just explored.            

            A eukaryotic genome is transcribed into pre-mRNA and is then catalyzed by RNA polymerase⁸. In typical transcription once this occurs, it is crucial the chromatin structure of the replicated sequence is restored⁸. If not, then risk for cryptic promoter sequences increases which is known to age cells due to altering normal nucleosome arrangment⁸.  Senescence cells attempt to prevent this damage by ceasing to replicate so they secrete soluble factors to increase immunity, but high exposure of the secretion can cause aging or damage in the still replicating, young cells⁸. Senescence will no longer undergo normal transcription due to risk damage or age, while normal cells carry out transcription and under senescence secretion may have a high chance of a cryptic promoter opening up and altering the RNA⁸.  Figure g shows proliferating cells to emit a strong signal, while senescent cells barely emitted a signal⁸.

The researchers previous work in yeast and worms, results showed prevention of age-related intragenic cryptic transcription⁸. A gene body trimethylation mark on lysine 36 of histone H3 (H3K36me3) showed increased transcriptional stability, while in mice embryonic stem cells, DNA in cooperation with H3K36 methylation resulted in prevention of cryptic transcription⁸. In this, It was found that younger genes have a strict regulation to ensure transcription runs smoothly⁸.

References

• 1 Fridlyanskaya, I., Alekseenko, L., Nikolsky, N. Senescence as a general cellular response to stress: A mini-review. Experimental Gerontology. 2015; 72: 124-128
• 2 Cellular Senescence. Cell Signaling Technology,https://www.cellsignal.com/science-resources/overview-of-cellular-senescence
• 3 Wikipedia contributors. G₀ phase 2024;https://en.wikipedia.org/wiki/G0_phase
• 4 OpenStaxCollege. Biology- Eukaryotic Transcription Gene Regulation. 2012; Pressbooks,
• https://pressbooks-dev.oer.hawaii.edu/biology/chapter/eukaryotic-transcription-gene-regulation/
• 5 Baylor College of Medicine. Cryptic transcription, a novel phenomenon in mammalian stem  cells, linked to aging. 2021; ScienceDaily, https://www.sciencedaily.com/releases/2021/08/210802160654.htm.
• 6 Nahas, K. “cryptic transcription”: How aging cells express fragments of genes, TheScientist, https://www.the-scientist.com/cryptic-transcription-how-aging-cells-express-fragments-of-genes-71056 (Accessed: 22 June 2024).
• 7 Wei, W., Hennig, B., Wang, J., Zhang, Y., Piazza,I. et al. (2019) Chromatin-sensitive cryptic promoters putatively drive expression of alternative protein isoforms in yeast, Genome research. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886497/.
• 8 Sen, P., Donahue, G., Li, C., Eggervari, G., Yang, N., Lan, Y., Robertson, N., Shah, P.p., Kerkoven, E., Schultz, D.C., et al. (2023). Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging. Nat Aging 3, 402-417. 10.1038/s43587-023-00384-