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Genome-wide mapping indicates that p73 and p63 co-occupy target sites and have similar dna-binding profiles in vivo.

ABSTRACT: BACKGROUND:The p53 homologs, p63 and p73, share approximately 85% amino acid identity in their DNA-binding domains, but they have distinct biological functions. PRINCIPAL FINDINGS:Using chromatin immunoprecipitation and high-resolution tiling arrays covering the human genome, we identify p73 DNA binding sites on a genome-wide level in ME180 human cervical carcinoma cells. Strikingly, the p73 binding profile is indistinguishable from the previously described binding profile for p63 in the same cells. Moreover, the p73:p63 binding ratio is similar at all genomic loci tested, suggesting that there are few, if any, targets that are specific for one of these factors. As assayed by sequential chromatin immunoprecipitation, p63 and p73 co-occupy DNA target sites in vivo, suggesting that p63 and p73 bind primarily as heterotetrameric complexes in ME180 cells. CONCLUSIONS:The observation that p63 and p73 associate with the same genomic targets suggest that their distinct biological functions are due to cell-type specific expression and/or protein domains that involve functions other than DNA binding.

SUBMITTER: Yang A

PROVIDER: S-EPMC2904373 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Genome-wide mapping indicates that p73 and p63 co-occupy target sites and have similar dna-binding profiles in vivo.

Yang Annie A Zhu Zhou Z Kettenbach Arminja A Kapranov Philipp P McKeon Frank F Gingeras Thomas R TR Struhl Kevin K

PloS one 20100714 7

<h4>Background</h4>The p53 homologs, p63 and p73, share approximately 85% amino acid identity in their DNA-binding domains, but they have distinct biological functions.<h4>Principal findings</h4>Using chromatin immunoprecipitation and high-resolution tiling arrays covering the human genome, we identify p73 DNA binding sites on a genome-wide level in ME180 human cervical carcinoma cells. Strikingly, the p73 binding profile is indistinguishable from the previously described binding profile for p63 ...[more]

PMID: 20644729

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Project description:The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets of p53 and they appear to aid p53 in promoting growth arrest and apoptosis. However, the question of p53/p63/p73 regulating the miRNA processing complex has not been addressed in depth so far. Comparative/computational genomic analysis was performed using Target scan, Mami, and Diana software to identify miRNAs that regulate the miRNA processing complex. Here, I present evidence for the first time that the tumor suppressors p53, p63, and p73 function as both positive and negative regulators of the miRNA processing components. Curated p53-dependent miRNA expression data was used to identify p53-miRs that target the components of the miRNA-processing complex. This analysis suggests that most of the components (mRNAs' 3'UTR) of the miRNA processing complex are targeted by p53-miRs. Remarkably, this data revealed the conserved nature of p53-miRs in targeting a number of components of the miRNA processing complex. p53/p73/p63 appears to regulate the major components of the miRNA processing, such as Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. In particular, p53/p73/p63 appears to regulate the processing of miRNAs, such as let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21. Interestingly, there seems to be a phenotypic similarity between p63(-/-) and dicer(-/-) mice, suggesting that p63 and dicer could regulate each other. In addition, p63, p73, and the DGCR8 proteins contain a conserved interaction domain. Further, promoters of a number of components of the miRNA processing machinery, including dicer and P2P-R, contain p53-REs, suggesting that they could be direct transcriptional targets of p63/p73/p53. Together, this study provides mechanistic insights into how p53, p63, and p73 regulate the components of the miRNA processing; and how p53, TA-p63, and TA-p73 regulated miRNAs inhibit tumorigenesis, EMT, metastasis, and cancer stem cell proliferation.

Dataset Information

Genome-wide mapping indicates that p73 and p63 co-occupy target sites and have similar dna-binding profiles in vivo.

Publications

Genome-wide mapping indicates that p73 and p63 co-occupy target sites and have similar dna-binding profiles in vivo.

Similar Datasets

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