ALKBH5 controls the meiosis-coupled mRNA clearance in oocytes by removing the N ⁶-methyladenosine methylation.

Abstract

N⁶-methyladenosine (m⁶A) maintains maternal RNA stability in oocytes. One regulator of m⁶A, ALKBH5, reverses m⁶A deposition and is essential in RNA metabolism. However, the specific role of ALKBH5 in oocyte maturation remains elusive. Here, we show that Alkbh5 depletion causes a wide range of defects in oocyte meiosis and results in female infertility. Temporal profiling of the maternal transcriptomes revealed striking RNA accumulation in Alkbh5^-/- oocytes during meiotic maturation. Analysis of m⁶A dynamics demonstrated that ALKBH5-mediated m⁶A demethylation ensures the timely degradation of maternal RNAs, which is severely disrupted following Alkbh5^-/- depletion. A distinct subset of transcripts with persistent m⁶A peaks are recognized by the m⁶A reader IGF2BP2 and thus remain stabilized, resulting in impaired RNA clearance. Additionally, reducing IGF2BP2 in Alkbh5-depleted oocytes partially rescued these defects. Overall, this work identifies ALKBH5 as a key determinant of oocyte quality and unveil the facilitating role of ALKBH5-mediated m⁶A removal in maternal RNA decay.