{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T04:18:01Z","timestamp":1747196281947,"version":"3.40.5"},"reference-count":104,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T00:00:00Z","timestamp":1681344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Intragenic CpG dinucleotides are tightly conserved in evolution yet are also vulnerable to methylation-dependent mutation, raising the question as to why these functionally critical sites have not been deselected by more stable coding sequences. We previously showed in cell lines that altered exonic CpG methylation can modify promoter start sites, and hence protein isoform expression, for the human<jats:italic>TP53<\/jats:italic>tumor suppressor gene. Here we extend this work to the in vivo setting by testing whether synonymous germline modifications of exonic CpG sites affect murine development, fertility, longevity, or cancer incidence. We substituted the DNA-binding exons 5\u20138 of<jats:italic>Trp53<\/jats:italic>, the mouse ortholog of human<jats:italic>TP53<\/jats:italic>, with variant-CpG (either CpG-depleted or -enriched) sequences predicted to encode the normal p53 amino acid sequence; a control construct was also created in which all non-CpG sites were synonymously substituted. Homozygous<jats:italic>Trp53<\/jats:italic>-null mice were the only genotype to develop tumors. Mice with variant-CpG<jats:italic>Trp53<\/jats:italic>sequences remained tumor-free, but were uniquely prone to dental anomalies causing jaw malocclusion (p &lt; .0001). Since the latter phenotype also characterises murine Rett syndrome due to dysfunction of the trans-repressive MeCP2 methyl-CpG-binding protein, we hypothesise that CpG sites may exert non-coding phenotypic effects via pre-translational cis-interactions of 5-methylcytosine with methyl-binding proteins which regulate mRNA transcript initiation, expression or splicing, although direct effects on mRNA structure or translation are also possible.<\/jats:p>","DOI":"10.1371\/journal.pone.0284327","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T17:41:57Z","timestamp":1681407717000},"page":"e0284327","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synonymous alterations of cancer-associated Trp53 CpG mutational hotspots cause fatal developmental jaw malocclusions but no tumors in knock-in mice"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4640-0195","authenticated-orcid":true,"given":"Richard J.","family":"Epstein","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank P. Y.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Brink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5216-8815","authenticated-orcid":true,"given":"James","family":"Blackburn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,4,13]]},"reference":[{"key":"pone.0284327.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-24738-0_1","article-title":"Epigenetic Regulation.","volume":"879","author":"J Minarovits","year":"2016","journal-title":"Adv Exp Med Biol"},{"issue":"12","key":"pone.0284327.ref002","doi-asserted-by":"crossref","first-page":"e1005661","DOI":"10.1371\/journal.pgen.1005661","article-title":"DNA Methylation: Insights into Human Evolution.","volume":"11","author":"I 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