Regulation of telomere homeostasis and genomic stability in cancer by <i>N</i> <sup>6</sup>-adenosine methylation (m<sup>6</sup>A).
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34321211.
- Also identified by DOI 10.1126/sciadv.abg7073 and PMC identifier 8318370.
- Licence recorded as CC BY-NC.
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Abstract
The role of RNA methylation on <i>N</i> <sup>6</sup>-adenosine (m<sup>6</sup>A) in cancer has been acknowledged, but the underlying mechanisms remain obscure. Here, we identified homeobox containing 1 (<i>HMBOX1</i>) as an authentic target mRNA of m<sup>6</sup>A machinery, which is highly methylated in malignant cells compared to the normal counterparts and subject to expedited degradation upon the modification. m<sup>6</sup>A-mediated down-regulation of <i>HMBOX1</i> causes telomere dysfunction and inactivation of p53 signaling, which leads to chromosome abnormalities and aggressive phenotypes. CRISPR-based, m<sup>6</sup>A-editing tools further prove that the methyl groups on <i>HMBOX1</i> per se contribute to the generation of altered cancer genome. In multiple types of human cancers, expression of the RNA methyltransferase <i>METTL3</i> is negatively correlated with the telomere length but favorably with fractions of altered cancer genome, whereas <i>HMBOX1</i> mRNA levels show the opposite patterns. Our work suggests that the cancer-driving genomic alterations may potentially be fixed by rectifying particular epitranscriptomic program.