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Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.

ABSTRACT: The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-apoptotic conditions) p53. Compared to the classical 'acute' p53 binding profile, 'chronic' p53 peaks were closely associated with CpG-islands. Furthermore, the chronic CpG-island binding of p53 conferred distinct expression patterns between senescent and pro-apoptotic conditions. Using the p53 targets seen in the chronic conditions together with external high-throughput datasets, we have built p53 networks that revealed extensive self-regulatory 'p53 hubs' where p53 and many p53 targets can physically interact with each other. Integrating these results with public clinical datasets identified the cancer-associated lipogenic enzyme, SCD, which we found to be directly repressed by p53 through the CpG-island promoter, providing a mechanistic link between p53 and the 'lipogenic phenotype', a hallmark of cancer. Our data reveal distinct phenotype associations of chronic p53 targets that underlie specific gene regulatory mechanisms.

SUBMITTER: Kirschner K

PROVIDER: S-EPMC4366240 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.

Kirschner Kristina K Samarajiwa Shamith A SA Cairns Jonathan M JM Menon Suraj S Pérez-Mancera Pedro A PA Tomimatsu Kosuke K Bermejo-Rodriguez Camino C Ito Yoko Y Chandra Tamir T Narita Masako M Lyons Scott K SK Lynch Andy G AG Kimura Hiroshi H Ohbayashi Tetsuya T Tavaré Simon S Narita Masashi M

PLoS genetics 20150319 3

The downstream functions of the DNA binding tumor suppressor p53 vary depending on the cellular context, and persistent p53 activation has recently been implicated in tumor suppression and senescence. However, genome-wide information about p53-target gene regulation has been derived mostly from acute genotoxic conditions. Using ChIP-seq and expression data, we have found distinct p53 binding profiles between acutely activated (through DNA damage) and chronically activated (in senescent or pro-ap ...[more]

PMID: 25790137

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Project description:BackgroundThe availability of genome and transcriptome sequences for a number of species permits the identification and characterization of conserved as well as divergent genes such as lineage-specific genes which have no detectable sequence similarity to genes from other lineages. While genes conserved among taxa provide insight into the core processes among species, lineage-specific genes provide insights into evolutionary processes and biological functions that are likely clade or species specific.ResultsComparative analyses using the Arabidopsis thaliana genome and sequences from 178 other species within the Plant Kingdom enabled the identification of 24,624 A. thaliana genes (91.7%) that were termed Evolutionary Conserved (EC) as defined by sequence similarity to a database entry as well as two sets of lineage-specific genes within A. thaliana. One of the A. thaliana lineage-specific gene sets share sequence similarity only to sequences from species within the Brassicaceae family and are termed Conserved Brassicaceae-Specific Genes (914, 3.4%, CBSG). The other set of A. thaliana lineage-specific genes, the Arabidopsis Lineage-Specific Genes (1,324, 4.9%, ALSG), lack sequence similarity to any sequence outside A. thaliana. While many CBSGs (76.7%) and ALSGs (52.9%) are transcribed, the majority of the CBSGs (76.1%) and ALSGs (94.4%) have no annotated function. Co-expression analysis indicated significant enrichment of the CBSGs and ALSGs in multiple functional categories suggesting their involvement in a wide range of biological functions. Subcellular localization prediction revealed that the CBSGs were significantly enriched in proteins targeted to the secretory pathway (412, 45.1%). Among the 107 putatively secreted CBSGs with known functions, 67 encode a putative pollen coat protein or cysteine-rich protein with sequence similarity to the S-locus cysteine-rich protein that is the pollen determinant controlling allele specific pollen rejection in self-incompatible Brassicaceae species. Overall, the ALSGs and CBSGs were more highly methylated in floral tissue compared to the ECs. Single Nucleotide Polymorphism (SNP) analysis showed an elevated ratio of non-synonymous to synonymous SNPs within the ALSGs (1.99) and CBSGs (1.65) relative to the EC set (0.92), mainly caused by an elevated number of non-synonymous SNPs, indicating that they are fast-evolving at the protein sequence level.ConclusionsOur analyses suggest that while a significant fraction of the A. thaliana proteome is conserved within the Plant Kingdom, evolutionarily distinct sets of genes that may function in defining biological processes unique to these lineages have arisen within the Brassicaceae and A. thaliana.

Project description:The reversible phosphorolysis of purine and pyrimidine nucleosides is an important biochemical reaction in the salvage pathway, which provides an alternative to the de novo purine and pyrimidine biosynthetic pathways. Structural studies in our laboratory and by others have revealed that only two folds exist that catalyse the phosphorolysis of all nucleosides, and provide the basis for defining two families of nucleoside phosphorylases. The first family (nucleoside phosphorylase-I) includes enzymes that share a common single-domain subunit, with either a trimeric or a hexameric quaternary structure, and accept a range of both purine and pyrimidine nucleoside substrates. Despite differences in substrate specificity, amino acid sequence and quaternary structure, all members of this family share a characteristic subunit topology. We have also carried out a sequence motif study that identified regions of the common subunit fold that are functionally significant in differentiating the various members of the nucleoside phosphorylase-I family. Although the substrate-binding sites are arranged similarly for all members of the nucleoside phosphorylase-I family, a comparison of the active sites from the known structures of this family indicates significant differences between the trimeric and hexameric family members. Sequence comparisons also suggest structural identity between the nucleoside phosphorylase-I family and both 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase and AMP nucleosidase. Members of the second family of nucleoside phosphorylases (nucleoside phosphorylase-II) share a common two-domain subunit fold and a dimeric quaternary structure, share a significant level of sequence identity (>30%) and are specific for pyrimidine nucleosides. Members of this second family accept both thymidine and uridine substrates in lower organisms, but are specific for thymidine in mammals and other higher organisms. A possible relationship between nucleoside phosphorylase-II and anthranilate phosphoribosyltransferase has been identified through sequence comparisons. Initial studies in our laboratory suggested that members of the nucleoside phosphorylase-II family require significant domain movements in order for catalysis to proceed. A series of recent structures has confirmed our hypothesis and provided details of these conformational changes. Structural studies of the nucleoside phosphorylases have resulted in a wealth of information that begins to address fundamental biological questions, such as how Nature makes use of the intricate relationships between structure and function, and how biological processes have evolved over time. In addition, the therapeutic potential of suppressing the nucleoside phosphorylase activity in either family of enzymes has motivated efforts to design potent inhibitors. Several research groups have synthesized a variety of nucleoside phosphorylase inhibitors that are at various stages of preclinical and clinical evaluation.

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Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.

Publications

Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53.

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