Duplex DNA and BLM regulate gate opening by the human TopoIIIα-RMI1-RMI2 complex

Julia A. M. Bakx, Andreas S. Biebricher, Graeme A. King, Panagiotis Christodoulis, Kata Sarlós, Anna H. Bizard, Ian D. Hickson, Gijs J. L. Wuite () and Erwin J. G. Peterman ()
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Julia A. M. Bakx: Vrije Universiteit Amsterdam
Andreas S. Biebricher: Vrije Universiteit Amsterdam
Graeme A. King: Vrije Universiteit Amsterdam
Panagiotis Christodoulis: Vrije Universiteit Amsterdam
Kata Sarlós: Department of Cellular and Molecular Medicine, University of Copenhagen
Anna H. Bizard: Department of Cellular and Molecular Medicine, University of Copenhagen
Ian D. Hickson: Department of Cellular and Molecular Medicine, University of Copenhagen
Gijs J. L. Wuite: Vrije Universiteit Amsterdam
Erwin J. G. Peterman: Vrije Universiteit Amsterdam

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Topoisomerase IIIα is a type 1A topoisomerase that forms a complex with RMI1 and RMI2 called TRR in human cells. TRR plays an essential role in resolving DNA replication and recombination intermediates, often alongside the helicase BLM. While the TRR catalytic cycle is known to involve a protein-mediated single-stranded (ss)DNA gate, the detailed mechanism is not fully understood. Here, we probe the catalytic steps of TRR using optical tweezers and fluorescence microscopy. We demonstrate that TRR forms an open gate in ssDNA of 8.5 ± 3.8 nm, and directly visualize binding of a second ssDNA or double-stranded (ds)DNA molecule to the open TRR-ssDNA gate, followed by catenation in each case. Strikingly, dsDNA binding increases the gate size (by ~16%), while BLM alters the mechanical flexibility of the gate. These findings reveal an unexpected plasticity of the TRR-ssDNA gate size and suggest that TRR-mediated transfer of dsDNA may be more relevant in vivo than previously believed.

Date: 2022
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DOI: 10.1038/s41467-022-28082-5

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