A Dual-activity Topoisomerase Complex Interacts with piRNA Machinery to Promote Transposon Silencing and Germ Cell Function

Topoisomerase 3 beta (Top3β) is the only eukaryotic dual-activity topoisomerase that can change topology for both DNA and RNA. Current evidence suggests that Top3β can facilitate transcription on DNA and translation of mRNAs. Top3β forms a complex with Tudor domain containing 3 (TDRD3), which interacts with the Fragile X Mental Retardation Protein (FMRP) to regulate mRNA translation. Top3β mutation in human has been linked to schizophrenia, autism, and cognitive impairment, whereas Top3β inactivation in mice results reduced lifespan and abnormal neurodevelopment. However, the mechanism of how Top3β maintains normal life-span and mental health remains largely unclear.
We have recently shown that the Top3β-TDRD3 complex interacts with the siRNA machinery to facilitate heterochromatin formation and transcriptional silencing of genes and transposable elements (TEs). PIWI-interacting RNAs (piRNAs) are the other major class of small RNAs that are germ-cell specific and suppresses TEs. Here we demonstrate the functions of Top3β biochemically and genetically interact with piRNA mediated machinery in germ cells. First, Top3β and Tdrd3 form stable complexes with the piRNA machinery, including PIWI, in germline tissues of both mouse and Drosophila. Second, mutation of Top3β results in de-silencing of multiple transposons in gonads. Third, Top3β and piRNA machinery genetically interact to suppress expression of TEs. Together, our data reveal a novel role of Top3β-TDRD3 complex—interacting with the piRNA machinery to promote silencing of TEs and germ cell function