Intro

P53 has been the most extensively studied protein related to cancer. I’ll try to be brief on what we’ve learned about it.

It is an tumor suppressor, mutations in p53 are prevalent among lots of cancer types. On average, one in two cancer patients will have a mutation in p53 (Joerger and Fersht 2008).
In recent years, the oncogenic role (or gain-of-function mutations) of p53 gains attention.

Network

figure from the paper by Vogelstein, Lane, and Levine (2000)

p53 is at the center of the network that receiving and transmitting multiple signals from various cell stress to downstream molecules. (Reinhardt and Schumacher 2012; Vogelstein, Lane, and Levine 2000)
- stress is mainly DNA damage.
downstream effects of p53 : cell growth suppression.
A transcription factor
p53 is maintained at low levels by negative regulations of mdm2.

Structure

Figure from this wiki page

homotetramer is the functional form
p53 consists 3 domains, they are
- trans-activation motif,
  - naive unfolded TAD
- p53 DNA-binding domain and
  - intrinsically unstable (compared to ancient versions: TP63, TP73)
  - as a result susceptible to mutations
  - 91.2% of all cancer related somatic mutations are in this domain( 5-8 exonic regions)(Kouidou, Malousi, and Maglaveras 2006)
  - all missense mutation hotspots are in this domain
- tetramerisation motif.
  - p53 functions in the form of homotetramer.

Recurrent Mutations & function analysis

Reported Hotspots

Missense hotspot mutations

- DNA binding  
    - DNA contact R248 R273  
    - binding surface R175H, G245S, R249S, and R282W  
- beta-sandwich
    - V143A, V157F, Y220C, and F270C destabilizing 
- Zinc ligand  
    - C242S R175H

reported missense mutation hotspots were confirmed in TCGA samples. Most of the TCGA projects were conducted after (Joerger and Fersht 2008)
- an exception is V143A, not observed in TCGA dataset
these mutations are analysed as loss-of-function effect

Reported hotspots(dashed lines) and hotspots in TCGA(points)

Nonsense hotspot mutation

- methylated CG sequence mutation
    - codon(#AA position) 158,196, 205, 298, 306, 213
- adjacent or 1~2base removed from methylation sites
    - 192, 204

The nonsense hotspot mutations in p53 is analysed and explained in this paper (Kouidou, Malousi, and Maglaveras 2006)
In summary of the paper, these hotspots are at or near methylation sites.
A table derived from the paper, showing the sequence pattern:

Table 7.
Frequency and sequence analysis of codons leading to nonsense mutations (more than 3 mutations/codon). On the left, sequences for which more than 10 nonsense mutations have been reported are shown; on the right, are sequences with less than 10 nonsense mutations. In bold are mutated bases included in the corresponding codons. Repeats are underlined; * and ** indicate CC → TT tandem mutations and palindromes, respectively. Potential methylation sites are indicated with small letters (CG and R/M are highlighted in yellow; none in grey background shading). R: repeat, M: methylation

nonsense hotspots in TCGA

each black dot is a nonsense mutation candidate site
all of the hotspots can be found in the above table.

Gain of function mutations

!!!may update this later.

Conclusion

missense mutation hotspots can be explained from the structural perspective.
nonsense mutation hotspots might be related to methylation and sequence context.
- I think “sequence context,such as methylation, creates nonsense mutation hotspots” is an more plausible explanation than “truncated p53 proteins are positively selected”

Reference

Joerger, Andreas C., and Alan R. Fersht. 2008. “Structural Biology of the Tumor Suppressor P53.” Annual Review of Biochemistry 77 (1): 557–82. doi:10.1146/annurev.biochem.77.060806.091238.

Kouidou, Sofia, Andigoni Malousi, and Nicos Maglaveras. 2006. “Methylation and Repeats in Silent and Nonsense Mutations of P53.” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 599 (1–2): 167–77. doi:10.1016/j.mrfmmm.2006.03.002.

Reinhardt, H. Christian, and Björn Schumacher. 2012. “The P53 Network: Cellular and Systemic DNA Damage Responses in Aging and Cancer.” Trends in Genetics 28 (3): 128–36. doi:10.1016/j.tig.2011.12.002.

Vogelstein, Bert, David Lane, and Arnold J. Levine. 2000. “Surfing the P53 Network.” Nature 408 (6810): 307–10. doi:10.1038/35042675.

case_study_p53

tc

2017-03-17