Topoisomerase 3ß is the major topoisomerase for mRNAs and linked to neurodevelopment and mental dysfunction

Abstract

Human cells contain five topoisomerases in the nucleus and cytoplasm, but which one is the major topoisomerase for mRNAs is unclear. To date, Top3 is the only known topoisomerase that possesses RNA topoisomerase activity, binds mRNA translation machinery and interacts with an RNA-binding protein, FMRP, to promote synapse formation; and Top3 gene deletion has been linked to schizophrenia. Here, we show that Top3 is also the most abundant mRNA-binding topoisomerase in cells. Top3, but not other topoisomerases, contains a distinctive RNA-binding domain; and deletion of this domain diminishes the amount of Top3 that associates with mRNAs, indicating that Top3 is specifically targeted to mRNAs by its RNA binding domain. Moreover, Top3 mutants lacking either its RNA-binding domain or catalytic residue fail to promote synapse formation, suggesting that Top3 requires both its mRNA-binding and catalytic activity to facilitate neurodevelopment. Notably, Top3 proteins bearing point mutations from schizophrenia and autism individuals are defective in association with FMRP; whereas one of the mutants is also deficient in binding mRNAs, catalyzing RNA topoisomerase reaction, and promoting synapse formation. Our data suggest that Top3 is the major topoisomerase for mRNAs, and requires both RNA binding and catalytic activity to promote neurodevelopment and prevent mental dysfunction.