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One Billion Years of P53/P63/P73 Evolution

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One Billion Years of P53/P63/P73 Evolution COMMENTARY One billion years of p53/p63/p73 evolution Vladimir A. Belyi and Arnold J. Levine1 Institute for Advanced Study, Princeton, NJ 08540 he report in this issue of PNAS by Joerger et al. (1) solves the structure of the p73 oligomer- ization domain that produces a Ttetrameric protein and compares this structure with p63 (closely related) and p53 (more distantly related). This pro- vides new information about the com- parative evolution of these three (p53, p63, and p73) proteins and more. The human genome contains three genes encoding the transcription factors p53, p63, and p73, which are closely re- lated paralogs with some similar and some diverse functions (Fig. 1A). p53 acts in somatic cells in response to stresses (such as DNA damage) that re- duce the fidelity of DNA replication and cell division, by initiating apoptosis, se- nescence or cell cycle arrest, providing a tumor suppressor function (2). Humans heterozygous for a p53 mutation de- velop a variety of cancers at early ages (3). p63 is one of the major transcrip- tion factors required for the develop- ment of epithelial cell layers. Humans Fig. 1. The domain structure of the p53 family proteins. (A) The domain organization of human p53, p63, carrying a mutation in one allele of this and p73 along with the p63/p73 ancestor proteins from Drosophila melanogaster and Caenorhabditis gene can have cleft palate, skeletal ab- elegans. The percentage of identity of the amino acids and their position in the domain are given for both normalities, and skin pathologies (EEC the DNA-binding domain and the oligomeric domain. (B) The structure of the oligomeric domain of p73 syndrome), but they do not develop can- from ref. 1. The H-2 helix stabilizes this p73 tetramer and is absent from the p53 tetramer. p63 and p73 are cers at high rates (4, 5). p73 is involved more closely related to each other than to p53 based on the primary, secondary, tertiary, and quaternary in the development of the central ner- structures of both the DNA-binding domains and the oligomerization domains. vous system and the immune system. It also responds to a subset of stress sig- nals observed with p53, initiating apop- sharing 55–87% homology, and the Dro- is in the cartilaginous fish (shark), where tosis, and in this sense p73 can back up sophila gene (dmp53) having 25% ho- a new p53 gene is observed along with a p53 in response to DNA damage (6). mology, whereas the C. elegans gene single p63/p73 ancestor gene (12). By Studies with knock-out mice have indi- (Cep-1) has 15% homology at the amino the appearance of bony fish (zebra fish) cated that p53, p63, and p73 can also acid level (12). Both invertebrate and all three genes, p53, p63, and p73, are play a role in germ-line surveillance of vertebrate proteins recognize and bind present and p53 has taken on its new fidelity (7–9), and p63 and p73 may be to the same DNA sequences that regu- functions ensuring the fidelity of somatic involved in aspects of tumor suppres- late some similar genes in these very cell division, an adaptation of the p63/ sion. p53 also is required for efficient diverse species, leading to apoptosis af- p73 ancestor genes’ role in the germ line implantation of embryos into the uterus ter a DNA-damaging event. dmp53 and (12). Within the higher vertebrates, p63 in mice (10) and humans (11). It is the Cep-1 play a central role in germ-line and p73 have taken on new functions in germ-line surveillance and implantation fidelity in response to a variety of stress development of tissues and organs, functions that result in strong evolution- signals (DNA damage, starvation, etc.). whereas p53 has become the guardian of ary selection pressures on this family of Most invertebrates harbor a single the somatic genome and a tumor sup- genes (12). The p53, p63, and p73 pro- p63/p73-like gene, with the earliest or- pressor. With the advent of employing teins are structurally related. They all ganism observed during evolution, the large numbers of stem cells and tissue have an amino-terminal transcriptional sea anemone, expressing this ancestor regeneration as a strategy for an organ- trans-activation domain linked to a gene in its germ cells. When exposed to ism’s growth, development, and mainte- DNA-binding domain, which is followed ultraviolet light, which happens when nance, there is a greater need for stem by an oligomerization domain (a tet- these organisms feed at the surface of cell surveillance to prevent cancers from ramer in vertebrates) and a carboxyl- the water, the p63/73 ancestor gene ini- arising. p53 evolved to fill this role. It is terminal regulatory region (Fig. 1A). tiates apoptosis to protect the germ line p63 and p73 have an extra SAM (sterile from mistakes (12). This means that the alpha motif) domain, which confers pro- structure and the functions of the p53 Author contributions: V.A.B. and A.J.L. wrote the paper. tein stability. The DNA-binding domains sister genes have been preserved for The authors declare no conflict of interest. of p53, p63, and p73 have been con- about one billion years. The first indica- See companion article on page 17705. served over long evolutionary time tion that this ancestor p63/p73 gene du- 1To whom correspondence should be addressed. E-mail: frames, with the three human paralogs plicated, separating into distinct entities, [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0910634106 PNAS ͉ October 20, 2009 ͉ vol. 106 ͉ no. 42 ͉ 17609–17610 Downloaded by guest on September 28, 2021 of some interest that p53 has recently mains (p63/p73 are 87% identical to explain this observation is that mu- been shown to regulate the efficiency of whereas p53/p63-p73 are 55–58% identi- tant p53 proteins form complexes with induced pluripotent stem cell production cal). This agrees well with the detection other transcription factors, such as p63 from differentiated cells (13–17) indicat- of the first p53 gene duplicating from a or p73, and either inactivate them or ing a new possible role for p53 in en- common p63/p73 ancestor gene in the change their patterns of transcription, forcing the direction of developmental altering the properties of the cancer cell. processes in a cell. There is an intimate Indeed, mutant p53/p73 complexes have relationship among p53, stem cell devel- been detected in cancer cells (21), and opment, and epigenetic regulation of Humans heterozygous an altered chemotherapeutic response these processes, and it began to evolve could be the result of an inactivation of in the fishes. for a p53 mutation p73 apoptotic functions (22). This is one The structure of the oligomerization of the phenotypes of mutant p53 in a domain of p73 (Fig. 1B) gives us new develop a variety of cancer cell. The Joerger et al. article information about the structural evolu- suggests that formation of this heterotet- tion of the three sister proteins and cancers at early ages. rameric mutant p53/p73 protein is not more (1). The p73 tetrameric domain, likely mediated by the oligomeric do- like the p53 oligomerization domain main, but elsewhere in the two proteins. If we wish to develop drugs that break (18), is a dimer of a dimer composed of evolutionary studies of the genomes of this complex and free p73 to act as apop- monomeric blocks containing a short fish (1, 12). totic mediator of chemotherapy (21–23) ␤-strand followed by an ␣-helix (H-1 Joerger et al. (1) go on to examine the exchange in vitro of p63 and p73 it will be useful to know the locations in helix). What is distinct about the p73 the proteins where they interact to form and the p63 oligomerization domain, monomeric units in the oligomerization domains to form hybrid proteins. This mixed tetramers. A common polymor- compared with p53, is the presence of phism in the domain of the p53 protein exchange is slow (Ϸ10 h at 37 °C) and an extra helical region (the H-2 helix) that connects the trans-activating do- does not occur with p53 monomers or that stabilizes the overall architecture of main with the DNA-binding domain the p73 (and presumably p63) tetramer. dimers (18). For several reasons this is (not in the oligomerization domain) can The H-2 helix acts as a clasp packing an important biological question that is affect the mutant p53/p73 heterodimer against the H-1 helix (Fig. 1B). In the not yet resolved. First, we would like to formation (23) consistent with all of absence of the H-2 helix the tetramer is know whether the combinations of these observations and suggesting a new much less stable, as measured by ther- mixed heteromeric p63/p73 exist in vivo location for protein–protein interactions. mal denaturation in differential scan- and have any functional significance. Although this question of a mutant p53 ning calorimetry. These structural There are multiple isoforms, or splice gain of function and its possible mecha- differences in the human oligomeriza- forms, of both proteins that could pro- nism remains unresolved, its importance tion domains of p63 and p73 (56% iden- duce a complex picture in development. for understanding both the poor out- tical at the amino acid level) separate Second, in cancers a mutant missense comes in cancers associated with mutant them from a more distant p53 (34–37% p53 protein can show a gain-of-function p53 and possible new methods of treat- identical to p63 and p73) as previously phenotype both in cell culture (19) and ment of cancers with mutant p53 makes observed with the DNA-binding do- in vivo (20).
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