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: 4.66). 01/2011; 6(1):2. DOI: 10.1186/1745-6150-6-2
Source: PubMed


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


Available from: Victor B Zhurkin
  • Source
    • "For example, G-quadruplexes are recognized and cleaved by the RAG1 protein (Nambiar et al. 2011) that evolved from transposase of the Transib family of DNA transposons (Kapitonov and Jurka 2005). Moreover, the p53 tumor suppressor protein that binds sites located inside Alu and L1 elements (Cui et al. 2011) can also strongly bind G-quadruplex DNA (Quante et al. 2012). Similarly, the multifunctional protein, Ku70, can bind cDNA of Ty1 yeast retrotransposon and simultaneously has high affinity to G-quadruplex DNA (Downs and Jackson 1999; Paramasivam et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A significant part of eukaryotic genomes is formed by transposable elements (TEs) containing not only genes but also regulatory sequences. Some of the regulatory sequences located within TEs can form secondary structures like hairpins or three-stranded (triplex DNA) and four-stranded (quadruplex DNA) conformations. This review focuses on recent evidence showing that G-quadruplex-forming sequences in particular are often present in specific parts of TEs in plants and humans. We discuss the potential role of these structures in the TE life cycle as well as the impact of G-quadruplexes on replication, transcription, translation, chromatin status, and recombination. The aim of this review is to emphasize that TEs may serve as vehicles for the genomic spread of G-quadruplexes. These non-canonical DNA structures and their conformational switches may constitute another regulatory system that, together with small and long non-coding RNA molecules and proteins, contribute to the complex cellular network resulting in the large diversity of eukaryotes.
    Full-text · Article · Sep 2015 · Chromosome Research
  • Source
    • "Based on ChIP-PET data generated with a combination of chromatin immunoprecipitation and paired-end tags sequencing methods, approximately 15% of p53-binding sites were found to reside within Alu elements [125]. Apart from those sites preexisting in the progenitors of several Alu subfamilies, the methylation and deamination resulting from the CG to TG transition could generate the CATG motifs attractive to p53 for binding in vivo [126]. Some Alu elements contain negative calcium response elements [127, 128], cholesteryl esterase transferase response elements [129–131], and so forth. "
    [Show abstract] [Hide abstract]
    ABSTRACT: DNA methylation primarily occurs on CpG dinucleotides and plays an important role in transcriptional regulations during tissue development and cell differentiation. Over 25% of CpG dinucleotides in the human genome reside within Alu elements, the most abundant human repeats. The methylation of Alu elements is an important mechanism to suppress Alu transcription and subsequent retrotransposition. Decades of studies revealed that Alu methylation is highly dynamic during early development and aging. Recently, many environmental factors were shown to have a great impact on Alu methylation. In addition, aberrant Alu methylation has been documented to be an early event in many tumors and Alu methylation levels have been associated with tumor aggressiveness. The assessment of the Alu methylation has become an important approach for early diagnosis and/or prognosis of cancer. This review focuses on the dynamic Alu methylation during development, aging, and tumor genesis. The cause and consequence of Alu methylation changes will be discussed.
    Full-text · Article · Aug 2014 · BioMed Research International
  • Source
    • "MIR elements are an ancient family of tRNA-derived SINEs [13,14], whose anomalous sequence-conservation levels among mammalian genomes were initially taken as evidence that they encode some unknown regulatory function [15]. Succeeding studies demonstrated that, in a number of individual cases, MIRs do in fact donate transcription-factor binding sites [16-20], enhancers [18,21,22], microRNAs [23,24] and cis natural antisense transcripts [25] to the human genome. The association of MIRs with tissue-specific expression, along with their propensity to be exapted as regulatory sequences, suggests to us the possibility that they might provide numerous tissue-specific regulatory sequences across the human genome [8]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Mammalian-wide interspersed repeats (MIRs) are the most ancient family of transposable elements (TEs) in the human genome. The deep conservation of MIRs initially suggested the possibility that they had been exapted to play functional roles for their host genomes. MIRs also happen to be the only TEs whose presence in-and-around human genes is positively correlated to tissue-specific gene expression. Similar associations of enhancer prevalence within genes and tissue-specific expression, along with MIRs’ previous implication as providing regulatory sequences, suggested a possible link between MIRs and enhancers. Results To test the possibility that MIRs contribute functional enhancers to the human genome, we evaluated the relationship between MIRs and human tissue-specific enhancers in terms of genomic location, chromatin environment, regulatory function, and mechanistic attributes. This analysis revealed MIRs to be highly concentrated in enhancers of the K562 and HeLa human cell-types. Significantly more enhancers were found to be linked to MIRs than would be expected by chance, and putative MIR-derived enhancers are characterized by a chromatin environment highly similar to that of canonical enhancers. MIR-derived enhancers show strong associations with gene expression levels, tissue-specific gene expression and tissue-specific cellular functions, including a number of biological processes related to erythropoiesis. MIR-derived enhancers were found to be a rich source of transcription factor binding sites, underscoring one possible mechanistic route for the element sequences co-option as enhancers. There is also tentative evidence to suggest that MIR-enhancer function is related to the transcriptional activity of non-coding RNAs. Conclusions Taken together, these data reveal enhancers to be an important cis-regulatory platform from which MIRs can exercise a regulatory function in the human genome and help to resolve a long-standing conundrum as to the reason for MIRs’ deep evolutionary conservation.
    Full-text · Article · May 2014 · Mobile DNA
Show more