Δημοσίευση

Li-Fraumeni and Li-Fraumeni-like syndrome mutations in p53 are associated with exonic methylation and splicing regulatory elements.

ΤίτλοςLi-Fraumeni and Li-Fraumeni-like syndrome mutations in p53 are associated with exonic methylation and splicing regulatory elements.
Publication TypeJournal Article
Year of Publication2009
AuthorsKouidou, S., Malousi A., & Maglaveras N.
JournalMol Carcinog
Volume48
Issue10
Pagination895-902
Date Published2009 Oct
ISSN1098-2744
Λέξεις κλειδιάCodon, CpG Islands, DNA Methylation, DNA Mutational Analysis, Enhancer Elements, Genetic, Exons, Humans, Li-Fraumeni Syndrome, Mutation, Regulatory Sequences, Nucleic Acid, RNA Splicing, Syndrome, Tumor Suppressor Protein p53
Abstract

Mutations in codon 133 of p53, which cause the loss of the Delta 133 isoform(s) expression, are very frequent in the Li-Fraumeni (LF) and Li-Fraumeni-like (LFL) syndromes. In sporadic cancers, silent p53 mutations are correlated with exonic splicing enhancers (ESEs) and exonic methylated sites. The present study shows that mutations in splice sites are also very frequent in LF/LFL syndromes, while missense mutations are less common compared to other familial or sporadic cancers (P = 0 in both cases). Furthermore, it is shown that the codons at which LF/LFL germline missense mutations occur, correlate with CpG-containing ESEs (r = 0.181, P = 0.014) which are all methylated in p53. While both silent and LF/LFL missense mutations correlate with SC35 motifs, only the latter are associated with SRp55. On the contrary, only silent mutations in sporadic cancers correlate with SF2/ASF motifs in p53. Moreover, 12.1% of LF/LFL missense mutations involve the formation of potential splice sites of considerable splicing scores. Finally, mutations that are not at, or adjacent to CpGs (+/-1 codon, 34% of all LF/LFL mutated sites), introduce considerable changes of the ESE scores (>1.3 score change). The above data verify that LF/LFL missense mutations probably result also in splicing deregulation, in addition to any changes of the protein function and are mostly associated with alterations of the exonic methylation landscape. Some of the ESEs affected in LF/LFL syndromes are also genetically unstable in sporadic cancers but non-CpG cytosine instability, which is predominantly associated with specific ESEs, is only common in sporadic cancers.

DOI10.1002/mc.20537
Alternate JournalMol. Carcinog.
PubMed ID19367569

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