K235 acetylation couples with PSPC1 to regulate the m⁶A demethylation activity of ALKBH5 and tumorigenesis.

Abstract

N6-methyladenosine (m⁶A) modification plays important roles in bioprocesses and diseases. AlkB homolog 5 (ALKBH5) is one of two m⁶A demethylases. Here, we reveal that ALKBH5 is acetylated at lysine 235 (K235) by lysine acetyltransferase 8 and deacetylated by histone deacetylase 7. K235 acetylation strengthens the m⁶A demethylation activity of ALKBH5 by increasing its recognition of m⁶A on mRNA. RNA-binding protein paraspeckle component 1 (PSCP1) is a regulatory subunit of ALKBH5 and preferentially interacts with K235-acetylated ALKBH5 to recruit and facilitate the recognition of m⁶A mRNA by ALKBH5, thereby promoting m⁶A erasure. Mitogenic signals promote ALKBH5 K235 acetylation. K235 acetylation of ALKBH5 is upregulated in cancers and promotes tumorigenesis. Thus, our findings reveal that the m⁶A demethylation activity of ALKBH5 is orchestrated by its K235 acetylation and regulatory subunit PSPC1 and that K235 acetylation is necessary for the m⁶A demethylase activity and oncogenic roles of ALKBH5.