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Li-Fraumeni Syndrome (LFS) results from heterozygous germline mutations of  TP53 , encoding a key transcriptional factor activated in response to DNA damage. We have recently shown, from a large LFS series, that dominant-negative missense mutations are the most clinically severe and, thanks to a new p53 functional assay in lymphocytes, that they alter the p53 transcriptional response to DNA damage more drastically than null mutations. In this study, we first confirmed this observation by performing the p53 functional assay in lymphocytes from 56  TP53  mutation carriers harbouring 35 distinct alterations. Then, to compare the impact of the different types of germline  TP53  mutations on DNA binding, we performed chromatin immunoprecipitation-sequencing (ChIP-Seq) in lymphocytes exposed to doxorubicin. ChIP-Seq performed in wild-type  TP53  control lymphocytes accurately mapped 1287 p53-binding sites. New p53-binding sites were validated using a functional assay in yeast. ChIP-Seq analysis of LFS lymphocytes carrying  TP53  null mutations (p.P152Rfs*18 or complete deletion) or the low penetrant ‘Brazilian’ p.R337H mutation revealed a moderate decrease of p53-binding sites (949, 580 and 620, respectively) and of ChIP-Seq peak depths. In contrast, analysis of LFS lymphocytes with  TP53  dominant-negative missense mutations p.R273H or p.R248W revealed only 310 and 143 p53-binding sites, respectively, and the depths of the corresponding peaks were drastically reduced. Altogether, our results show that  TP53  mutation carriers exhibit a constitutive defect of the transcriptional response to DNA damage and that the clinical severity of  TP53  dominant-negative missense mutations is explained by a massive and global alteration of p53 DNA binding.

Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage