A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.


Abstract

The TP53 gene is frequently mutated in human cancer. Research has focused predominantly on six major "hotspot" codons, which account for only ∼30% of cancer-associated p53 mutations. To comprehensively characterize the consequences of the p53 mutation spectrum, we created a synthetically designed library and measured the functional impact of ∼10,000 DNA-binding domain (DBD) p53 variants in human cells in culture and in vivo. Our results highlight the differential outcome of distinct p53 mutations in human patients and elucidate the selective pressure driving p53 conservation throughout evolution. Furthermore, while loss of anti-proliferative functionality largely correlates with the occurrence of cancer-associated p53 mutations, we observe that selective gain-of-function may further favor particular mutants in vivo. Finally, when combined with additional acquired p53 mutations, seemingly neutral TP53 SNPs may modulate phenotypic outcome and, presumably, tumor progression.

Submission Details

ID: axWiFkxq3

Submitter: Connie Wang

Submission Date: July 12, 2018, 11:33 a.m.

Version: 1

Publication Details
Kotler E;Shani O;Goldfeld G;Lotan-Pompan M;Tarcic O;Gershoni A;Hopf TA;Marks DS;Oren M;Segal E,Mol Cell (2018) A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. PMID:29979965
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1A1U 1997-12-16T00:00:00+0000 0 SOLUTION STRUCTURE DETERMINATION OF A P53 MUTANT DIMERIZATION DOMAIN, NMR, MINIMIZED AVERAGE STRUCTURE
1AIE 1997-04-17T00:00:00+0000 1.5 P53 TETRAMERIZATION DOMAIN CRYSTAL STRUCTURE
1C26 1999-07-22T00:00:00+0000 1.7 CRYSTAL STRUCTURE OF P53 TETRAMERIZATION DOMAIN
1DT7 2000-01-11T00:00:00+0000 0 SOLUTION STRUCTURE OF THE C-TERMINAL NEGATIVE REGULATORY DOMAIN OF P53 IN A COMPLEX WITH CA2+-BOUND S100B(BB)
1GZH 2002-05-22T00:00:00+0000 2.6 Crystal structure of the BRCT domains of human 53BP1 bound to the p53 tumor supressor
1GZH 2002-05-22T00:00:00+0000 2.6 Crystal structure of the BRCT domains of human 53BP1 bound to the p53 tumor supressor
1H26 2002-07-31T00:00:00+0000 2.24 CDK2/CyclinA in complex with an 11-residue recruitment peptide from p53
1HS5 2000-12-22T00:00:00+0000 0 NMR SOLUTION STRUCTURE OF DESIGNED P53 DIMER
1JSP 2001-08-17T00:00:00+0000 0 NMR Structure of CBP Bromodomain in complex with p53 peptide
1KZY 2002-02-08T00:00:00+0000 2.5 Crystal Structure of the 53bp1 BRCT Region Complexed to Tumor Suppressor P53

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
93.1 Cellular tumor antigen p53 Q9TTA1 P53_TUPBE
95.7 Cellular tumor antigen p53 P56424 P53_MACMU
95.7 Cellular tumor antigen p53 P61260 P53_MACFU
95.7 Cellular tumor antigen p53 P56423 P53_MACFA
95.2 Cellular tumor antigen p53 P13481 P53_CHLAE
100.0 Cellular tumor antigen p53 P04637 P53_HUMAN