DDX5 orchestrates RNA homeostasis to ensure oocyte developmental competence

Abstract Oocyte development requires tight regulation of transcription and RNA metabolism, which is coordinated by RNA-binding proteins, whose roles in mammalian oogenesis remain incompletely understood. Here, we identify the DEAD-box RNA helicase DDX5 as a key regulator of RNA homeostasis in oocytes. Oocyte-specific deletion of DDX5 leads to female sterility, which is characterized by defective chromatin remodeling, meiotic arrest, increased aneuploidy, and fertilization failure. Mechanistically, DDX5 maintains RNA homeostasis through three interconnected processes: (1) promoting transcription via interaction with RNA polymerase II in nonsurrounded nucleolus-stage germinal vesicle oocytes; (2) clearing retrotransposon RNAs to safeguard transcriptome integrity; and (3) supporting maternal mRNA storage by coordinating nuclear export, mitochondrial organization, and mitochondria-associated ribonucleoprotein domain assembly. Our study establishes DDX5 as a master regulator that integrates transcriptional and post-transcriptional programs to ensure oocyte competence and fertility.