MassIVE MSV000087179

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Direct interaction of tyrosyl DNA phosphodiesterase 1 with DNA ligase III catalytic domain is regulated by phosphorylation of its flexible N-terminus

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Description

Tyrosyl DNA phosphodiesterase 1 (TDP1) and DNA Ligase III (LigIII) are key enzymes in nuclear and mitochondrial single-strand break (SSB) repair pathways whereby TDP1 removes the 3-tyrosine residue remaining after degradation of a trapped DNA topoisomerase 1. Here we define a direct interaction between TDP1 catalytic domain and LigIII DNA binding domain (DBD) that is regulated by conformational changes in the unstructured TDP1 N-terminal region induced by phosphorylation and/or alterations in amino acid sequence. Full-length and N-terminally truncated TDP1 are more effective at correcting the defect in SSB repair of TDP1 null cells compared with full-length TDP1 with amino acid substitutions of an N-terminal serine residue that is phosphorylated in response to DNA damage. TDP1 forms a stable complex with LigIII170-755, full-length LigIII as well as full-length LigIII alone and in complex with XRCC1. Homodimerization of LigIII BRCT domains links two LigIII-TDP1 heterodimers. Small angle X-ray scattering and negative stain electron microscopy combined with mapping of the interacting regions, identify a TDP1/LigIII compact dimer of heterodimers in which the two LigIII catalytic cores are positioned in the center, whereas two TDP1 molecules are located at the edges of the core complex formed by the LigIII DBD and the TDP1 catalytic domain flanked by highly flexible regions that can interact with other repair proteins and the SSB. As TDP1- LigIII repairs adducts caused by TOP1 cancer chemotherapy inhibitors, the defined interaction architecture and regulation informs on how this enzyme complex functions and is regulated in non-malignant and cancer cells. [doi:10.25345/C5TF8G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: human tyrosyl DNA phosphodiesterase 1 phosphorylation, DNA damage

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Principal Investigators:
(in alphabetical order) 		Alan E Tomkinson, University of New Mexico, USA
Submitting User: bbudnik
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