Article

Impact of Alu repeats on the evolution of human p53 binding sites

Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Biology Direct (Impact Factor: 4.04). 01/2011; 6:2. DOI: 10.1186/1745-6150-6-2
Source: PubMed

ABSTRACT 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, however. We sought to understand whether the p53 REs also reside in transposable elements and particularly in the most-abundant Alu repeats.
We 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.
The 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.

Download full-text

Full-text

Available from: Victor B Zhurkin, Aug 14, 2015
0 Followers
 · 
115 Views
  • Source
    • "Moreover, an increased level of Alu RNA has been evidenced in hepatocellular carcinoma [137]. Cui et al., hypothesized that p53 binding to Alu elements, plus the transcriptional repression can change the expression of the host genes through steric interaction between RNA polymerase II, which is responsible for host gene expression, and RNA polymerase III that ensures Alu transcription [127]. This hypothesis has to be demonstrated as well as its consequences with respect to cancer onset and/or its development. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transposable elements are present in almost all genomes including that of humans. These mobile DNA sequences are capable of invading genomes and their impact on genome evolution is substantial as they contribute to the genetic diversity of organisms. The mobility of transposable elements can cause deleterious mutations, gene disruption and chromosome rearrangements that may lead to several pathologies including cancer. This mini-review aims to give a brief overview of the relationship that transposons and retrotransposons may have in the genetic cause of human cancer onset, or conversely creating protection against cancer. Finally, the cause of TE mobility may also be the cancer cell environment itself.
    Biochimica et Biophysica Acta 09/2012; 1835(1):28-35. DOI:10.1016/j.bbcan.2012.09.001 · 4.66 Impact Factor
  • Gastroenterology 01/2011; 140(5). DOI:10.1016/S0016-5085(11)62355-X · 13.93 Impact Factor
Show more