Functional analysis of the TTF complex and its role in neurodevelopmental diseases

• Applicant: Professor Dr. Utz Fischer
• Subject Area: General Genetics and Functional Genome Biology ; Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271023333

Topoisomerases are enzymes believed to act predominantly, if not exclusively, on DNA substrates in cells of all kingdoms. It was therefore a surprise when two labs, including ours, provided evidence that eukaryotic topoisomerase TOP3ß is a cytosolic RNA binding protein that exhibits enzymatic activity on RNA substrates in vitro. Our biochemical studies have further shown that TOP3ß forms together with TDRD3, a scaffolding protein, and FMRP, affected in Fragile X mental retardation syndrome (FXS), an as yet unknown trimeric complex in vivo. This unit, which we have named TOP3ß-TDRD3-FMRP (TTF) complex, is recruited to mRNPs via the exon junction complex (EJC) in a sequence independent manner. The biochemical composition of TTF-containing mRNPs and their association with polysomes further suggests that they are engaged in the pioneer round of translation. However, neither the in vivo RNA targets of the TTF complex nor its regulatory mode of action on RNA are known. Interestingly, deletion of the TOP3ß-gene is associated with schizophrenia and intellectual disability. It is therefore possible that the etiologies of schizophrenia and FXS intersect at the post-transcriptional regulation of RNA molecules associated with TOP3ß and FMRP. This project aims to elucidate the role of TTF in RNA metabolism by a) identifying the RNA targets of the TTF complex in vivo and b) determining its catalytic and/or regulatory function in RNA metabolism. These studies will also help to c) shed light on a potential RNA-based etiology of neuropsychiatric disorders.

• DFG Programme: Research Grants