Premature polyadenylation of MAGI3 is associated with diminished N[superscript 6]-methyladenosine in its large internal exon

Abstract

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[superscript 6]-methyladenosine (m[superscript 6]A). In breast cancer cells that upregulate MAGI3[superscript pPA], m[superscript 6]A levels in the large internal exon of MAGI3 are significantly reduced compared to cells that do not express MAGI3[superscript pPA]. We further find that MAGI3[superscript pPA] transcripts are significantly depleted of m[superscript 6]A modifications, in contrast to highly m6A-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[superscript 6]A levels in these exons are reduced in pPA-activated breast cancer cells relative to untransformed mammary cells. Our study suggests that m6A may play a role in regulating intronic pPA of MAGI3 and possibly other TSGs, warranting further investigation.