Analysis of p53–RNA interactions in cultured human cells

Riley, Kasandra; Maher, L. James

doi:10.1016/j.bbrc.2007.08.181

Cited by 9 publications

(6 citation statements)

References 31 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The altered, now more populated conformational state of the p53 could favor an altered p53-RE. In this regard, the recent results of Riley et al related to p53-RNA interactions are interesting: although recombinant p53 protein binds RNA in a sequence-nonspecific mode [65] , RNA binding is prevented by post-translational p53 modifications [66] , again suggesting that phosphorylation alters the distribution of the ensemble. An insight into the effect of protein factors on the differential activation of p53 target genes was also recently provided, particularly into the CDK-module of the human Mediator complex which functions as stimulus-specific positive coregulators of p21 transcription [67] .…”

Section: Discussionmentioning

confidence: 98%

Cooperativity Dominates the Genomic Organization of p53-Response Elements: A Mechanistic View

Pan

Nussinov

2009

PLoS Comput Biol

View full text Add to dashboard Cite

p53-response elements (p53-REs) are organized as two repeats of a palindromic DNA segment spaced by 0 to 20 base pairs (bp). Several experiments indicate that in the vast majority of the human p53-REs there are no spacers between the two repeats; those with spacers, particularly with sizes beyond two nucleotides, are rare. This raises the question of what it indicates about the factors determining the p53-RE genomic organization. Clearly, given the double helical DNA conformation, the orientation of two p53 core domain dimers with respect to each other will vary depending on the spacer size: a small spacer of 0 to 2 bps will lead to the closest p53 dimer-dimer orientation; a 10-bp spacer will locate the p53 dimers on the same DNA face but necessitate DNA looping; while a 5-bp spacer will position the p53 dimers on opposite DNA faces. Here, via conformational analysis we show that when there are 0–2 bp spacers, p53-DNA binding is cooperative; however, cooperativity is greatly diminished when there are spacers with sizes beyond 2 bp. Cooperative binding is broadly recognized to be crucial for biological processes, including transcriptional regulation. Our results clearly indicate that cooperativity of the p53-DNA association dominates the genomic organization of the p53-REs, raising questions of the structural organization and functional roles of p53-REs with larger spacers. We further propose that a dynamic landscape scenario of p53 and p53-REs can better explain the selectivity of the degenerate p53-REs. Our conclusions bear on the evolutionary preference of the p53-RE organization and as such, are expected to have broad implications to other multimeric transcription factor response element organization.

show abstract

Section: Discussionmentioning

confidence: 98%

Cooperativity Dominates the Genomic Organization of p53-Response Elements: A Mechanistic View

Pan

Nussinov

2009

PLoS Comput Biol

View full text Add to dashboard Cite

show abstract

“…73 In addition, evidence suggests that the interaction of p53 with a consensus DNA sequence stabilizes this protein and inhibits its aggregation 74 ; however, it is also possible that longer DNA chains could lead to polymerization. 75 Although the interaction between p53 and RNA has been reported, [76][77][78] aggregates produced by this interaction have not yet been identified. Poly-adenylated RNA has been found in aggresomes that contain several key proteins (including p53) involved in cancer and neurodegenerative diseases.…”

Section: Molecular Partners Involved In P53 Aggregationmentioning

confidence: 99%

The aggregation of mutant p53 produces prion-like properties in cancer

Rangel

Costa

Vieira

et al. 2014

Prion

View full text Add to dashboard Cite

“…The p53 protein itself might be an attractive candidate since it has been shown to contain two distinct nucleic acid‐binding domains: (1) a DNA‐binding core domain which is responsible for recognition of the p53 duplex DNA consensus sequence in promoters of target genes and (2) a second, highly basic nucleic acid‐binding domain at the CTD, that binds with high affinity to single‐ and double‐stranded DNA and RNA, although without sequence preference . However, specific p53‐RNA interactions have hitherto never been detected in vivo , possibly due to the high number of posttranslational modifications present in p53 that would prevent RNA binding . It is also possible that tRNA fragment levels regulate the activity of kinases that then phosphorylate p53 upon oxidative stress, such as Ataxia Telangiectasia mutated (ATM) kinase or affect p53 turnover by acting on its negative regulator MDM2 .…”

Section: Searching For the Mediator Between Trna Fragments And P53 Phmentioning

confidence: 99%

CLP1 as a novel player in linking tRNA splicing to neurodegenerative disorders

et al. 2014

View full text Add to dashboard Cite

Defects in RNA metabolic pathways are well-established causes for neurodegenerative disorders. Several mutations in genes involved in pre-messenger RNA (pre-mRNA) and tRNA metabolism, RNA stability and protein translation have been linked to motor neuron diseases. Our study on a mouse carrying a catalytically inactive version of the RNA kinase CLP1, a component of the tRNA splicing endonuclease complex, revealed a neurological disorder characterized by progressive loss of lower spinal motor neurons. Surprisingly, mutant mice accumulate a novel class of tRNA-derived fragments. In addition, patients with homozygous missense mutations in CLP1 (R140H) were recently identified who suffer from severe motor-sensory defects, cortical dysgenesis and microcephaly, and exhibit alterations in transfer RNA (tRNA) splicing. Here, we review functions of CLP1 in different RNA pathways and provide hypotheses on the role of the tRNA splicing machinery in the generation of tRNA fragments and the molecular links to neurodegenerative disorders. We further immerse the biology of tRNA splicing into topics of (t)RNA metabolism and oxidative stress, putting forward the idea that defects in tRNA processing leading to tRNA fragment accumulation might trigger the development of neurodegenerative diseases.

show abstract

Analysis of p53–RNA interactions in cultured human cells

Cited by 9 publications

References 31 publications

Cooperativity Dominates the Genomic Organization of p53-Response Elements: A Mechanistic View

Cooperativity Dominates the Genomic Organization of p53-Response Elements: A Mechanistic View

The aggregation of mutant p53 produces prion-like properties in cancer

CLP1 as a novel player in linking tRNA splicing to neurodegenerative disorders

Contact Info

Product

Resources

About