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Mol Cell. 2018 Jul 5;71(1):178-190.e8. doi: 10.1016/j.molcel.2018.06.012.

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

Author information

1
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel.
2
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
3
Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel.
4
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: moshe.oren@weizmann.ac.il.
6
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: eran.segal@weizmann.ac.il.

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.

PMID:
29979965
DOI:
10.1016/j.molcel.2018.06.012
[Indexed for MEDLINE]
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