N-methyladenosine (mA) maintains maternal RNA stability in oocytes. One regulator of mA, ALKBH5, reverses mA 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 mA dynamics demonstrated that ALKBH5-mediated mA demethylation ensures the timely degradation of maternal RNAs, which is severely disrupted following Alkbh5 depletion. A distinct subset of transcripts with persistent mA peaks are recognized by the mA 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 mA removal in maternal RNA decay.
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| http://dx.doi.org/10.1038/s41467-023-42302-6 | DOI Listing |
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