Exploring the biological roles of DHX36, a DNA/RNA G-quadruplex helicase, highlights functions in male infertility: A comprehensive review.

It is estimated that 15 % of couples at reproductive age worldwide suffer from infertility, approximately 50 % of cases are caused by male factors. Significant progress has been made in the diagnosis and treatment of male infertility through assisted reproductive technology and molecular genetics methods. However, there is still inadequate research on the underlying mechanisms of gene regulation in the process of spermatogenesis. Guanine-quadruplexes (G4s) are a class of non-canonical secondary structures of nucleic acid commonly found in genomes and RNAs that play important roles in various biological processes. Interestingly, the DEAH-box helicase 36 (DHX36) displays high specificity for the G4s which can unwind both DNA G4s and RNA G4s enzymatically and is highly expressed in testis, thereby regulating multiple cellular functions including transcription, pre-mRNA splicing, translation, telomere maintenance, genomic stability, and RNA metabolism in development and male infertility. This review provides an overview of the roles of G4s and DHX36 in reproduction and development. We mainly focus on the potential role of DHX36 in male infertility. We also discuss possible future research directions regarding the mechanism of spermatogenesis mediated by DHX36 through G4s in spermatogenesis-related genes and provide new targets for gene therapy of male infertility.