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  • Mascot ID score br R ALPNNTSSSPQPK K

    2020-08-12

    Mascot ID score
    (R)ALPNNTSSSPQPK(K)
    (K)TYQGSYGFR(L)
    (R)ALPNNTSSSPQPK(K)
    (K)TYQGSYGFR(L)
    pre-mRNA for splicing and mutant protein expression, which in turn results in drug resistance in cancer cells heterozygously carrying TP53 R273H mutation. Both accumulation of genetic mutations and dysre-gulated RNA processing occur in cancer cells, and it has become in-creasingly clear that the latter contributes key components of cancerous behaviors and tumor progression. Recent studies showed that RNA methylation converting adenosine into m6A, and preferential pre-mRNA splicing brought about as a consequence of enhanced pre-mRNA recognition and processing by YTHDF1, YTHDF2 and other m6A-readers, can globally either upregulate or down-regulate expression of genes, including NANOG, POU5F1, KLF4, SOX2, c-MYC, EGFR, ASB2 and RARA, in ways that enrich cancer stem cells and promote tumor progression [49,50]. Our present study, for the first time, indicates that methylation of a single transited adenosine in a mutant codon of pre-mRNA can determine mutant protein expression from heterozygous TP53 R273H mutation. To wit, selective expression of the R273H mu-tant protein in cancer cells relies on the m6A at codon 273, and relevant pre-mRNA structure, which together confer preference for binding to spliceosome and splicing [51]. G-to-A transition is the most common Angiotensin II substitution in gene mutation, and has been reported in other codons (R175H, R248Q) of TP53 missense mutations, as well as in many other genes [7,9,52]. Whether or not m6A production in these cases also leads to preferential splicing to regulate mutant protein ex-pression needs to be investigated in further studies. 
    TP53 missense mutation is an attractive specific target for im-proving cancer treatments, and abolishing preferential p53 mutant protein expression might prove to be more an efficacious strategy thereto. DNA damage stress in cancer cells exposed to anticancer drugs can upregulate expression of mutant proteins, such as R273H, when mutated genes coding for them are present, which at minimum in-variably results in drug resistance, thereby compromising the efficacy of treatments [53] (Fig. 1, Table 1). We hereby advance suppression of m6A levels as a possible approach for quashing mutant p53 protein expression while restoring wt p53 protein expression and function, so as to efficaciously sensitize cancer cells that carry heterozygous R273H mutation (Fig. 1, Table 1). Our current studies also revealed that glycosphingolipids, in parti-cular Gb3, can upregulate the expression of METTL3 via promotion of cSrc/β-catenin signaling, thereby enhancing RNA methylation so as to facilitate or favor mutant protein expression and consequent drug re-sistance. Devising suitable ways of targeting these pivotal pathways, perhaps most profitably in combination, should provide the basis for clinically viable and valuable therapeutic approaches that will improve treatments of cancers found to carry comparably activating mutations of tumor suppressor genes.
    Altogether, our study uncovers a novel function of a pre-mRNA m6A in determining mutant protein expression, in this case for the TP53 R273H mutation. Moreover, we found that ceramide glycosylation in
    cross-talk with RNA methylation contributes to mutant protein ex-pression and cancer drug resistance in cancer cells carrying this mis-sense mutation. Therefore, suppressing m6A-RNA methylation or/and ceramide glycosylation might constitute a specific and highly effica-cious approach for targeting R273H TP53 missense mutation.
    Author disclose statement
    Authors claim no competing financial interests exist.
    Author contributions
    Acknowledgements
    This work was supported by National Institutes of Health Grants (R15CA167476) from the National Cancer Institute and (P20GM103424-11) from the National Institute of General Medical Sciences (to Y.Y.L.). This work was also partially supported by National Institutes of Health Grant (P20GM121293) from the National Institute of General Medical Sciences (to A.J.T.).
    References
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