Isoform-Specific Roles of Mutant p63 in Human Diseases

Osterburg, Christian; Osterburg, Susanne; Zhou, Huiqing; Missero, Caterina; Dötsch, Volker

doi:10.3390/cancers13030536

Cited by 16 publications

(10 citation statements)

References 149 publications

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“…7 ). The dramatic effect of activated TAp63α for female fertility has also been demonstrated by the identification of mutations that create constitutively tetrameric (and therefore activated) TAp63α forms in human patients suffering from premature ovarian insufficiency [ 163 , 194 – 197 ].…”

Section: Isoformsmentioning

confidence: 99%

Structural diversity of p63 and p73 isoforms

Osterburg

Dötsch

2022

Cell Death Differ

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The p53 protein family is the most studied protein family of all. Sequence analysis and structure determination have revealed a high similarity of crucial domains between p53, p63 and p73. Functional studies, however, have shown a wide variety of different tasks in tumor suppression, quality control and development. Here we review the structure and organization of the individual domains of p63 and p73, the interaction of these domains in the context of full-length proteins and discuss the evolutionary origin of this protein family. Facts Distinct physiological roles/functions are performed by specific isoforms. The non-divided transactivation domain of p63 has a constitutively high activity while the transactivation domains of p53/p73 are divided into two subdomains that are regulated by phosphorylation. Mdm2 binds to all three family members but ubiquitinates only p53. TAp63α forms an autoinhibited dimeric state while all other vertebrate p53 family isoforms are constitutively tetrameric. The oligomerization domain of p63 and p73 contain an additional helix that is necessary for stabilizing the tetrameric states. During evolution this helix got lost independently in different phylogenetic branches, while the DNA binding domain became destabilized and the transactivation domain split into two subdomains. Open questions Is the autoinhibitory mechanism of mammalian TAp63α conserved in p53 proteins of invertebrates that have the same function of genomic quality control in germ cells? What is the physiological function of the p63/p73 SAM domains? Do the short isoforms of p63 and p73 have physiological functions? What are the roles of the N-terminal elongated TAp63 isoforms, TA* and GTA?

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Section: Isoformsmentioning

confidence: 99%

Structural diversity of p63 and p73 isoforms

Osterburg

Dötsch

2022

Cell Death Differ

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“…In previous reports, heterozygous variants in the human TP63 gene were mostly shown to impair epidermal development and to cause multiple organ malformations, including 5 syndromic and 2 nonsyndromic disorders ( 25 ). Interestingly, a relationship has been identified between C-terminal variations of the TP63 gene and POI ( 26 – 29 ).…”

Section: Introductionmentioning

confidence: 99%

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis

Huang¹,

Zhao²,

Yang³

et al. 2023

Journal of Clinical Investigation

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The transcription factor p63 guards genome integrity in the female germline, and its mutations have been reported in patients with premature ovarian insufficiency (POI). However, the precise contribution of the TP63 gene to the pathogenesis of POI needs to be further determined. Here, in 1,030 Chinese patients with POI, we identified 6 heterozygous mutations of the TP63 gene that impaired the C-terminal transactivation-inhibitory domain (TID) of the TAp63α protein and resulted in tetramer formation and constitutive activation of the mutant proteins. The mutant proteins induced cell apoptosis by increasing the expression of apoptosis-inducing factors in vitro. We next introduced a premature stop codon and selectively deleted the TID of TAp63α in mice and observed rapid depletion of the p63 +/ Δ TID mouse oocytes through apoptosis after birth. Finally, to further verify the pathogenicity of the mutation p.R647C in the TID that was present in 3 patients, we generated p63 +/R647C mice and also found accelerated oocyte loss, but to a lesser degree than in the p63 +/ Δ TID mice. Together, these findings show that TID-related variants causing constitutive activation of TAp63α lead to POI by inducing oocyte apoptosis, which will facilitate the genetic diagnosis of POI in patients and provide a potential therapeutic target for extending female fertility.

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“…In contrast to the tumour suppressor p53, p63 is rarely mutated in cancer [3]. In accordance with its function in the development of epithelial structures heterozygous dominant-negative p63 mutations are associated with distinct developmental disorders in humans [4][5][6] that feature at least one of three phenotypical hallmarks: ectodermal dysplasia (ED), limb defects, and orofacial clefting (OFC). The ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome (OMIM: 604292) presents the prototype of mutant p63 disorders as the patients exhibit all three hallmarks.…”

Section: Introductionmentioning

confidence: 99%

Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree

et al. 2023

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The transcription factor p63 shares a high sequence identity with the tumour suppressor p53 which manifests itself in high structural similarity and preference for DNA sequences. Mutations in the DNA binding domain (DBD) of p53 have been studied in great detail, enabling a general mechanism-based classification. In this study we provide a detailed investigation of all currently known mutations in the p63 DBD, which are associated with developmental syndromes, by measuring their impact on transcriptional activity, DNA binding affinity, zinc binding capacity and thermodynamic stability. Some of the mutations we have further characterized with respect to their ability to convert human dermal fibroblasts into induced keratinocytes. Here we propose a classification of the p63 DBD mutations based on the four different mechanisms of DNA binding impairment which we identified: direct DNA contact, zinc finger region, H2 region, and dimer interface mutations. The data also demonstrate that, in contrast to p53 cancer mutations, no p63 mutation induces global unfolding and subsequent aggregation of the domain. The dimer interface mutations that affect the DNA binding affinity by disturbing the interaction between the individual DBDs retain partial DNA binding capacity which correlates with a milder patient phenotype.

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Isoform-Specific Roles of Mutant p63 in Human Diseases

Cited by 16 publications

References 149 publications

Structural diversity of p63 and p73 isoforms

Structural diversity of p63 and p73 isoforms

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis

Disease-related p63 DBD mutations impair DNA binding by distinct mechanisms and varying degree

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