ALKBH5-dependent m6A demethylation controls splicing and stability of long 3′-UTR mRNAs in male germ cells

TLDR

N6‑methyladenosine (m6A) is a widespread RNA modification that is removed by the demethylase ALKBH5. This study provides the first molecular characterization of an Alkbh5 knockout mouse model. Loss of ALKBH5‑mediated m6A demethylation leads to improper splicing and accelerated degradation of long 3′‑UTR transcripts in male germ cells, disrupting spermatogenesis and male fertility.

Abstract

Significance N6-methyladnosine (m6A) represents one of the most common RNA modifications. Biochemical analyses have identified ALKBH5 as an eraser of m6A. The present study represents the first molecular characterization of the Alkbh5 knockout mouse model. Our data associate m6A erasure with mRNA length control. Specifically, proper m6A demethylation is required for correct splicing and selective degradation of longer 3′-UTR transcripts, which are abundant in mitotic and meiotic male germ cells, but these longer 3′-UTR transcripts become rapidly degraded in the haploid male germ cells. Aberrant m6A levels in spermatogenic cells are incompatible with normal spermatogenesis and male fertility.