p53 has been called the “Guardian of the genome” and is commonly known as a tumor-suppressor gene – a gene that suppresses the formation of cancer. Normally, the cell expresses low levels of the p53 protein, but if the genome is damaged, p53 levels rise and in turn activate several programs that will arrest the cell cycle and attempt to repair the DNA damage. If the genome cannot be repaired, p53 will then activate programmed cell death and the cell will die rather than pass on the damage to future generations.
p53 brings about these responses to DNA damage either by activating pre-existing proteins, or by specific binding to promoters or introns (the p53 element) of various target genes involved in cell cycle arrest, DNA repair, and cell suicide.
Well, guess what? It turns out that our friend the Alu element is poised to generate these p53 binding sites with a little help from cytosine deamination. This was shown in a recent study entitled, “Methylation and deamination of CpGs generate p53-binding sites on a genomic scale” by Tomasz Zemojtel, Szymon M. Kielbasa, Peter F. Arndt, Ho-Ryun Chung andMartin Vingron. Let me simply provide a few excerpts:
Our findings indicate that Alu sequences can serve as templates for the generation of p53- binding-sites on a genome-wide scale.
Thus, we conclude that methylation and deamination of cytosines generates a high number of preferred p53-binding sites in Alu elements, some of which were recruited to regulate target gene expression.
Finally, we used a statistical model to identify and characterize 20-mers in the human genome that lie on the fastest evolutionary trajectories of p53-site formation. Up to ~151 000 20-mers resided in the highest probability range and required only one cytosine deamination to become a p53 site. As expected, most of these (~119 000) were located in Alu sequences and ~10 000 resided in the non-repetitive portion of the genome.
And here is the basic conclusion:
Our findings strongly indicate that the formation of p53- binding sites by CpG deamination, in particular in Alu repeats but also in non-repetitive DNA, is an important evolutionary process. Alu repeats, which amplified to over one million copies, harbor one-third of the total number of CpGs in the human genome, resulting from which, most Alus are transcriptionally silenced by methylation. Because Alu elements are associated with gene-rich regions, the process of cytosine deamination is capable of transforming numerous silent Alus into functional regulatory elements. As we pointed out here, this process has assigned a role for Alus in spreading of p53-binding sites and in recruiting new target genes to the p53 regulatory network in a species-specific manner.
Let’s add this up. We’ve seen that the Alu element, which was in effect contained within the SRP (a device that is as ancient as the ribosome), has played an important role in primate and human evolution. It has likely reformatted the genome, spreading REST binding sites around to help facilitate brain evolution. And with the help of the most common mutation in mammals, cytosine deamination, it has spread and created binding sites for two transcription factors crucial to development, the retinoic acid receptor and Pax6, and now we see the Alu elements spreading and creating p53 sites to fine tune the genomic surveillance pathways of primate cells. It’s no wonder the authors of the p53 study conclude that “deamination of CpGs constitutes a universal mechanism for generation of different transcription-factor-binding sites in Alus.”
Luck? Or is it nudging?
Anyway, let me again quote myself from around 2002:
A second possible explanation was that cytosine was chosen because of its predisposition to undergo deamination. This explanation may also intersect with the hypothesis of necessity, as a good designer often finds ways to turn a “design problem” into an opportunity. In this case, let me propose that cytosine, far from being something any engineer would replace, may actually have played an instrumental role in the front-loading of evolution. Put simply, C-to-T transitions, as a function of deamination, may have posed a form of “direction” on evolution.