Premature polyadenylation of MAGI3 is associated with diminished N6-methyladenosine in its large internal exon

In cancer, tumor suppressor genes (TSGs) are frequently truncated, causing their encoded products to be non-functional or dominant-negative. We previously showed that premature polyadenylation (pPA) of MAGI3 truncates the gene, switching its functional role from a TSG to a dominant-negative oncogene. Here we report that MAGI3 undergoes pPA at the intron immediately downstream of its large internal exon, which is normally highly modified by N-6-methyladenosine (m(6)A). In breast cancer cells that upregulate MAGI3(pPA), m(6)A levels in the large internal exon of MAGI3 are significantly reduced compared to cells that do not express MAGI3(pPA). We further find that MAGI3(pPA) transcripts are significantly depleted of m(6)A modifications, in contrast to highly m(6)A-modified full-length MAGI3 mRNA. Finally, we analyze public expression data and find that other TSGs, including LATS1 and BRCA1, also undergo intronic pPA following large internal exons, and that m(6)A levels in these exons are reduced in pPA-activated breast cancer cells relative to untransformed mammary cells. Our study suggests that m(6)A may play a role in regulating intronic pPA of MAGI3 and possibly other TSGs, warranting further investigation.