Topoisomerase 3β 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, Top3β 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 Top3β gene deletion has been linked to schizophrenia. Here, we show that Top3β is also the most abundant mRNA-binding topoisomerase in cells. Top3β, but not other topoisomerases, contains a distinctive RNA-binding domain; and deletion of this domain diminishes the amount of Top3β that associates with mRNAs, indicating that Top3β is specifically targeted to mRNAs by its RNA binding domain. Moreover, Top3β mutants lacking either its RNA-binding domain or catalytic residue fail to promote synapse formation, suggesting that Top3β requires both its mRNA-binding and catalytic activity to facilitate neurodevelopment. Notably, Top3β 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 Top3β is the major topoisomerase for mRNAs, and requires both RNA binding and catalytic activity to promote neurodevelopment and prevent mental dysfunction.

The many lives of type IA topoisomerases

“…Consistent with this, copy number variants and de novo mutations in TOP3B have been linked to an increased risk of neurodevelopmental and cognitive disorders, including autism and schizophrenia (68,(166)(167)(168)(169). The involvement of TOP3B in cognition is likely conserved across species because TOP3B has been shown to be essential for correct synaptic formation in both mice and flies (67,166). These phenotypes, also observed when TOP1 and TOP2B are defective, suggest that TOP3B has a role in releasing topological constraints associated with transcription (170).…”

“…Indeed, the TOP3B gene resides on chromosome 22q11.2 in the human genome, a region frequently affected by deletions or duplications leading to congenital heart disease, facial malformation and cognitive dysfunction (68,(161)(162)(163)(164)(165). Consistent with this, copy number variants and de novo mutations in TOP3B have been linked to an increased risk of neurodevelopmental and cognitive disorders, including autism and schizophrenia (68,(166)(167)(168)(169). The involvement of TOP3B in cognition is likely conserved across species because TOP3B has been shown to be essential for correct synaptic formation in both mice and flies (67,166).…”

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

“…and Top3b have been linked to autism 106,156,207,[227][228][229][230] . Top3b has topoisomerase activity on both DNA and RNA 207,228 and is the major RNA topoisomerase for mRNAs 231 . Significantly, independent labs have found that Top3b is in a complex with a tudor-domain protein, Tdrd3, and FMRP 207,228,232 .…”

Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-linked RNA and DNA Breaks

“…Human TOP3B remained remarkably understudied until the recent discovery that it can act as a Type IA topoisomerase for both DNA and RNA (Ahmad et al, 2017a;Ahmad et al, 2017b;Ahmad et al, 2016;Stoll et al, 2013;Xu et al, 2013). Although TOP3B is not essential in flies or mice, Top3B knockout mice develop autoimmunity (Kwan et al, 2007), infertility (Kwan et al, 2003), have reduced lifespan (Kwan and Wang, 2001), abnormal neurodevelopment and defective synapse formation (Ahmad et al, 2017a;Ahmad et al, 2017b;Xu et al, 2013). In humans, TOP3B genomic deletion has been linked with Schizophrenia in a Northern Finnish subpopulation (Stoll et al, 2013).…”