Evolutionary conservation and somatic mutation hotspot maps of p53: correlation with p53 protein structural and functional features
Abstract
Missense mutations in p53 frequently occur at 'hotspot' amino acids which are highly conserved and represent regions of structural or functional importance. Using the p53 mutation database and the p53 DNA sequences for 11 species, we more precisely defined the relationships among conservation, mutation frequency and protein structure. We aligned the p53 sequences codon-by-codon and determined the degree of substitution among them. As a whole, p53 is evolving at an average rate for a mammalian protein-coding gene. As expected, the DNA binding domain is evolving more slowly than the carboxy and amino termini. A detailed map of evolutionary conservation shows that within the DNA binding domain there are repeating peaks and valleys of higher and lower evolutionary constraint. Mutation hotspots were identified by comparing the observed distribution of mutations to the pattern expected from a random multinomial distribution. Seventy-three hotspots were identified; these 19% of codons account for 88% of all reported p53 mutations. Both high evolutionary constraint and mutation hotspots are noted at amino acids close to the protein-DNA interface and at others more distant from DNA, often buried within the core of the folded protein but sometimes on its surface. The results indicate that targeting highly conserved regions for mutational and functional analysis may be efficient strategies for the study of cancer-related genes.
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TP53 mutations in glioblastoma are mostly point mutations that lead to high expression of gain-of-function oncogenic variants of the p53 protein.
“TP53 mutations in GBM are mostly point mutations that lead to a high expression of a gain of function (GOF) oncogenic variants of the p53 protein.”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [61]
More than 25% of TP53 missense mutations occur within 6 hotspots between exons 4-8: R273, R248 (class I, DNA contact mutations) R175, G245, R282, and R249 (class II, conformational mutations).
“More than 25% of TP53 missense mutations occur within 6 “hotspots” between exons 4–8: R273, R248 (class I, DNA contact mutations) R175, G245, R282, and R249 (class II, conformational mutations) (Figure 3) [61].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [61]
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- Authors
- Walker, D. R., Bond, J. P., Tarone, R. E., Harris, C. C., Makalowski, W., Boguski, M. S., & Greenblatt, M. S.
- Affiliations
- National Institutes of Health (US)
- University of Vermont (US)
- Venue
- Oncogene
- Published
- 1999-01-07
- Volume
- 18
- Issue
- 1
- Pages
- 211-218
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2325557141
- Cited by
- 198
- References
- 28
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 5 · 2021: 2 · 2020: 6 · 2019: 2 · 2018: 4 · 2017: 8 · 2016: 6 · 2015: 6 · 2014: 5 · 2013: 2 · 2012: 7
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- p53, missense mutations, mutational hotspots, evolutionary conservation, protein evolution rate, DNA-binding domain, protein-DNA interface, codon substitution, protein structure, somatic mutations, cancer genes
- MeSH terms
- Chromosome Mapping, Mutation, Protein Conformation, Tumor Suppressor Protein p53, Evolution, Molecular
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