Let’s say for a minute that you are a cell and you are getting old, this might be a sign that cellular senescence is nearby. The word senescence comes from the Latin word “senex”, which translates to “old man” (Kamal et al., 2020). More specifically, cellular senescence is when you, as a cell, cannot be prepared anymore so that you can enter the process of cell division, so you stop dividing permanently (Kamal et al., 2020). What could happen to you as you get older is that your DNA might get damaged, your telomeres might get shorter or not work as well as they should, or genes that lead to cancer by promoting uncontrolled cellular growth (oncogenes) might get activated (Kamal et al., 2020). These could all lead to your cellular senescence.
This is not the same as if you were in a G0 phase of the cell cycle, which is a phase you can end up in if regardless of your age if there is a actual problem in you at cellular checkpoints (Sun and Buttitta, 2017). The G0 phase is when your cell cycle is temporarily stopped (arrested) for various reasons, including you not needing to divide, there being a problem with you, or you lacking nutrients (Sun and Buttitta, 2017). If this problem is fixed, then you can enter the cell cycle again, if you are in G0 (Sun and Buttitta, 2017). However, if the problem cannot be fixed, then you enter senescence and you no longer divide until the immune system clears you out years later (Sun and Buttitta, 2017).
Let’s now assume for a second that you are a promoter sequence in DNA . You are the region of DNA that helps determine where the starting point of a gene and the beginning of where RNA polymerase should start transcribing the DNA (Wikimedia Team, 2025). Let’s also assume you are a cryptic promoter, which means that you are still a promoter, but a promoter that is more difficult for RNA polymerase to find compared to normal promoters (Kudo et al., 2021).
If you ever find yourself in the interesting circumstance that you are cryptic promoter that has been found by RNA polymerase to be copied, then you might end up altering the normal functioning of a cell (Kudo et al., 2021). This happens because cryptic promoters (you) can activate previously inactive DNA that has the potential to affect the inner workings of a cell (Kudo et al., 2021). You are also more common in older people because older people tend to have more of their DNA damaged and/or they have shorter telomeres.
This results in higher likelihood of cryptic promoters like yourself getting activated by RNA polymerases (Kudo et al., 2021). Another problem with cryptic promoters is that they can be located at incorrect parts of DNA (for example, the middle of DNA as opposed to the beginning, where the correct promoter is) and if RNA polymerase binds to it, then RNA sequences could be made that cause the incorrect kind of protein to be made (Kudo et al., 2021). This could have detrimental effects on the body that can exacerbate the effects of aging. This is why it is important to study cryptic promoters.
In proliferative cells, DNA transcription is upregulated and downregulated based on which stage of cell cycle the cell is in (Clayton, 2000). In the beginning of the cell cycle, the cell is in the G1 phase, and DNA transcription is upregulated (Clayton, 2000). This is because the DNA will need the transcribed information in the next phase of the cell cycle to be able to duplicate itself in the S phase of the cell cycle. When the cell actually gets to the S phase, the process of transcription is downregulated because DNA transcription and replication are happening at the same time (Clayton, 2000).
If DNA transcription and translation both happen at the same time with both of them happening at full speed, then there is a chance that DNA from both processes might collide with one another (Clayton, 2000). The G2 phase is a combination of upregulation and downregulation (Clayton, 2000). Genes that will allow the cell to enter mitosis maturely and facilitate chromosome segregation are upregulated, while genes that would cause the cell to enter mitosis prematurely are downregulated (Clayton, 2000).
During mitosis, DNA transcription is downregulated because the DNA from transcription have a risk of colliding with DNA and parts of the cell that going through major changes in mitosis (Clayton, 2000). If a proliferative cell starts to age or begins to struggle surviving in its environment right after mitosis or during the G1 phase of the cell cycle, then the cell can end up entering a dormant phase called G0. Here, the cell is no longer proliferative, but not senescent yet. They are quiescent, which means that their cell cycle has temporarily been stopped due to an issue with the cell. If the problem is resolved, then the cell continues the cell cycle.
If the issue of concern cannot be fixed, then the cell becomes senescent, which means it cannot go back into the cell cycle and remains in G0 (for months or years) until it completely dies. In both the quiescent and senescent phases of G0, DNA Transcription is downregulated (Sen et al., 2023). This because the genes that make RNA are now repressed. Also, pocket proteins influence transcription factors called “E2F”, which lead to genes that control cell division and RNA transcription and the pocket proteins also help repress E2Fs ability to lead to cell division and RNA transcription (Sen et al., 2023).
All in all, senescent cells, unlike their proliferative counterparts, do not go back and forth between upregulation and downregulation (Sen et al., 2023). Their RNA transcription is always downregulated because they don’t need to divide anymore. This is the most important difference in DNA transcription between proliferative and senescent cells.
Both normal and cryptic translation can occur in both proliferative and senescent cells (Starck & Shastri, 2016). However, normal DNA translation is more common in proliferative cells and cryptic DNA translation is more common in senescent cells (Starck & Shastri, 2016). Cryptic DNA translation can be differentiated from normal DNA translation because the results of cryptic DNA translation are lot shorter and more likely to code for genes with an incorrect or unknown function (Starck & Shastri, 2016).
When comparing senescent cells to proliferative cells, it can also be seen that there are differences in the types of histones found in senescent cells vs proliferative cells (Paluvai et al., 2020). Compared to proliferative cells, senescent cells tend to have less canonical (sequence preserving histones found in the synthesis stage of the cell cycle) histones (Paluvai et al., 2020). When compared again proliferative cells, it can also be seen that histone hyperacetylation is a feature that is more likely to be present in senescent cells (Paluvai et al., 2020).
Senescent cells can have both histone acetylation and histone deactelytion (Paluvai et al., 2020). Histone acetylation/deacetylation leading to senescence depends on which one it is that leads to senescence. In certain histones, it is acetylation that leads to senescence and in other histones it is deacetylation (Paluvai et al., 2020). There are certain histones that end up making senescent phenotypes in cells when their amounts are changed (for example: reduced H3K36me3 and increased H3K9la.) Both reduced H3K36me3 and increased H3K9la lead to transcriptional silencing, which then leads to cell senescence (Paluvai et al., 2020). Histone variants that are associated with senescence (for example: H2A.J and H3.3) are found abundantly in cells (Contrepois et al., 2017). Most histone changes involving making cell more senescent involve transcriptional silencing, but a minority of them involve transcriptional expression (Contrepois et al., 2017).
Under proliferative conditions, H2A.J is not a promoter or enhancer as its levels are usually kept low enough for it not have much of a promoter or enhancer effect (Contrepois et al., 2017). However, under senescent conditions, this histone variant usually is a promoter for senescence and certain types of cancer (Contrepois et al., 2017). H3.3, another histone variant, functions both as a promoter and an enhancer and it helps stabilize DNA that is being replicated in proliferative cells (Duarte et al., 2014). Under senescent conditions, H3.3 is can be cut off or overexpressed, which leads to advancement of secensent conditions (Duarte et al., 2014). However, what makes H3.3 unique is that the optimum amount of H3.3 (not much or not to less) can be used to regulate and slow down senescence in cancer therapies (Duarte et al., 2014).
In conclusion of all research, we explored the difference between proliferative and senescent cells with regards to cryptic transcription, histone acetylation and variants, and whether those histones are promoters or enhancers based on the senescence status of the cell.
References – Unfortunately, I wasn’t able to add hanging indents because WordPress does not support it.
Contrepois K., Coudereau C., Benayoun B. A., Schuler N., Roux P., Bischof O., Courbeyrette R., Carvalho C., Thuret J., Ma Z., Derbois C., Nevers M., Volland H., Redon C. E., Bonner W. M., Deleuze J., Wiel C., Bernard D., Snyder M. P., Rübe C. E., Olaso R., Fenaille F., & Mann C. (2017). Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression. Nature Communications, 8(1), Page. 10.1038/ncomms14995
Clayton D. A. (2000). Transcription and replication of mitochondrial DNA. Human Reproduction, 15(suppl 2), 11-17. 10.1093/humrep/15.suppl_2.11
Duarte L. F., Young A. R. J., Wang Z., Wu H., Panda T., Kou Y., Kapoor A., Hasson D., Mills N. R., Ma’ayan A., Narita M., & Bernstein E. (2014). Histone H3.3 and its proteolytically processed form drive a cellular senescence programme. Nature Communications, 5(1), Page. 10.1038/ncomms6210
Kudo H., Matsuo M., Satoh S., Hata T., Hachisu R., Nakamura M., Yamamoto Y. Y., Kimura H., Matsui M., & Obokata J. (2021). Cryptic promoter activation occurs by at least two different mechanisms in the Arabidopsis genome. The Plant Journal, 108(1), 29-39. 10.1111/tpj.15420
L; S. (2020). States of G0 and the proliferation-quiescence decision in cells, tissues and during development. PubMed, https://pubmed.ncbi.nlm.nih.gov/28695955/
Paluvai H., Di Giorgio E., & Brancolini C. (2020). The Histone Code of Senescence. Cells, 9(2), 466. 10.3390/cells9020466
P; M. (2017). Aging of the cells: Insight into cellular senescence and detection Methods. PubMed, https://pubmed.ncbi.nlm.nih.gov/32800277/
Projects C. (2001, December 15). Promoter (genetics) – Wikipedia. Wikimedia, https://en.wikipedia.org/wiki/Promoter_(genetics)
Sen P., Donahue G., Li C., Egervari G., Yang N., Lan Y., Robertson N., Shah P. P., Kerkhoven E., Schultz D. C., Adams P. D., & Berger S. L. (2023). Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging. Nature Aging, 3(4), 402-417. 10.1038/s43587-023-00384-3
Starck S. R., & Shastri N. (2016). Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance. Immunological Reviews, 272(1), 8-16. 10.1111/imr.12434
Becoming Dr. Osman Inac 