Abstract
BackgroundThe p53 tumor suppressor protein is involved in a complicated regulatory network, mediating expression of ~1000 human genes. Recent studies have shown that many p53 in vivo binding sites (BSs) reside in transposable repeats. The relationship between these BSs and functional p53 response elements (REs) remains unknown, however. We sought to understand whether the p53 REs also reside in transposable elements and particularly in the most-abundant Alu repeats.ResultsWe have analyzed ~160 functional p53 REs identified so far and found that 24 of them occur in repeats. More than half of these repeat-associated REs reside in Alu elements. In addition, using a position weight matrix approach, we found ~400,000 potential p53 BSs in Alu elements genome-wide. Importantly, these putative BSs are located in the same regions of Alu repeats as the functional p53 REs - namely, in the vicinity of Boxes A/A' and B of the internal RNA polymerase III promoter. Earlier nucleosome-mapping experiments showed that the Boxes A/A' and B have a different chromatin environment, which is critical for the binding of p53 to DNA. Here, we compare the Alu-residing p53 sites with the corresponding Alu consensus sequences and conclude that the p53 sites likely evolved through two different mechanisms - the sites overlapping with the Boxes A/A' were generated by CG → TG mutations; the other sites apparently pre-existed in the progenitors of several Alu subfamilies, such as AluJo and AluSq. The binding affinity of p53 to the Alu-residing sites generally correlates with the age of Alu subfamilies, so that the strongest sites are embedded in the 'relatively young' Alu repeats.ConclusionsThe primate-specific Alu repeats play an important role in shaping the p53 regulatory network in the context of chromatin. One of the selective factors responsible for the frequent occurrence of Alu repeats in introns may be related to the p53-mediated regulation of Alu transcription, which, in turn, influences expression of the host genes.ReviewersThis paper was reviewed by Igor B. Rogozin (nominated by Pavel A. Pevzner), Sandor Pongor, and I. King Jordan.
Highlights
The p53 tumor suppressor protein is involved in a complicated regulatory network, mediating expression of ~1000 human genes
We found that the genes which are up- and down-regulated by p53 do differ in the spacer length: S = 0 is predominant for the up-regulated genes, while S = 3 bp is over-represented for the downregulated genes [4]
Comparing the sequences of the p53 sites with their counterparts in the Alu consensus sequences, the authors detected multiple CG dinucleotides occurring at the positions that correspond to the CATG tetramer in the p53 sites. They proposed that the methylation and deamination of cytosine that results in the CG ® TG transition could generate the CATG motifs attractive to p53 for binding in vivo. (Independently, we proposed the same mechanism for thousands of predicted p53 binding sites (BSs) residing in Alu repeats genome-wide [15].) This mechanism, ostensibly differs from the one proposed earlier for the ERV LTR families by Haussler and coauthors [14], who argued that the p53 BSs are likely present in progenitor LTRs, not generated through mutations
Summary
The p53 tumor suppressor protein is involved in a complicated regulatory network, mediating expression of ~1000 human genes. Recent studies have shown that many p53 in vivo binding sites (BSs) reside in transposable repeats. The relationship between these BSs and functional p53 response elements (REs) remains unknown, . We sought to understand whether the p53 REs reside in transposable elements and in the most-abundant Alu repeats. P53 is one of the best-known tumor suppressor proteins, and is involved in an amazingly complicated regulatory network [1,2,3]. As a consequence of this degeneracy, the human genome contains enormous numbers of potential p53 BSs. The functional significance of the vast majority of these sites remains unknown,
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