Structural and mechanistic insight into Holliday-junction dissolution by topoisomerase IIIα and RMI1

Nicolas Bocquet; Anna H Bizard; Wassim Abdulrahman; Nicolai B Larsen; Mahamadou Faty; Simone Cavadini; Richard D Bunker; Stephen C Kowalczykowski; Petr Cejka; Ian D Hickson; Nicolas H Thomä

doi:10.1038/nsmb.2775

Structural and mechanistic insight into Holliday-junction dissolution by topoisomerase IIIα and RMI1

Nicolas Bocquet, Anna H Bizard, Wassim Abdulrahman, Nicolai B Larsen, Mahamadou Faty, Simone Cavadini, Richard D Bunker, Stephen C Kowalczykowski, Petr Cejka, Ian D Hickson, Nicolas H Thomä

46 Citationer (Scopus)

Abstract

Repair of DNA double-strand breaks via homologous recombination can produce double Holliday junctions (dHJs) that require enzymatic separation. Topoisomerase IIIα (TopIIIα) together with RMI1 disentangles the final hemicatenane intermediate obtained once dHJs have converged. How binding of RMI1 to TopIIIα influences it to behave as a hemicatenane dissolvase, rather than as an enzyme that relaxes DNA topology, is unknown. Here, we present the crystal structure of human TopIIIα complexed to the first oligonucleotide-binding domain (OB fold) of RMI1. TopIII assumes a toroidal type 1A topoisomerase fold. RMI1 attaches to the edge of the gate in TopIIIα through which DNA passes. RMI1 projects a 23-residue loop into the TopIIIα gate, thereby influencing the dynamics of its opening and closing. Our results provide a mechanistic rationale for how RMI1 stabilizes TopIIIα-gate opening to enable dissolution and illustrate how binding partners modulate topoisomerase function.

Originalsprog	Engelsk
Tidsskrift	Nature Structural and Molecular Biology
Vol/bind	21
Udgave nummer	3
Sider (fra-til)	261-8
Antal sider	8
ISSN	1545-9993
DOI	https://doi.org/10.1038/nsmb.2775
Status	Udgivet - mar. 2014

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10.1038/nsmb.2775

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abstract = "Repair of DNA double-strand breaks via homologous recombination can produce double Holliday junctions (dHJs) that require enzymatic separation. Topoisomerase IIIα (TopIIIα) together with RMI1 disentangles the final hemicatenane intermediate obtained once dHJs have converged. How binding of RMI1 to TopIIIα influences it to behave as a hemicatenane dissolvase, rather than as an enzyme that relaxes DNA topology, is unknown. Here, we present the crystal structure of human TopIIIα complexed to the first oligonucleotide-binding domain (OB fold) of RMI1. TopIII assumes a toroidal type 1A topoisomerase fold. RMI1 attaches to the edge of the gate in TopIIIα through which DNA passes. RMI1 projects a 23-residue loop into the TopIIIα gate, thereby influencing the dynamics of its opening and closing. Our results provide a mechanistic rationale for how RMI1 stabilizes TopIIIα-gate opening to enable dissolution and illustrate how binding partners modulate topoisomerase function.",

keywords = "Amino Acid Sequence, Binding Sites, Carrier Proteins, Catalytic Domain, Crystallography, X-Ray, DNA Breaks, Double-Stranded, DNA Topoisomerases, Type I, DNA, Cruciform, DNA, Single-Stranded, Gene Deletion, Humans, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Oligonucleotides, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Solubility",

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AU - Bocquet, Nicolas

AU - Bizard, Anna H

AU - Abdulrahman, Wassim

AU - Larsen, Nicolai B

AU - Faty, Mahamadou

AU - Cavadini, Simone

AU - Bunker, Richard D

AU - Kowalczykowski, Stephen C

AU - Cejka, Petr

AU - Hickson, Ian D

AU - Thomä, Nicolas H

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N2 - Repair of DNA double-strand breaks via homologous recombination can produce double Holliday junctions (dHJs) that require enzymatic separation. Topoisomerase IIIα (TopIIIα) together with RMI1 disentangles the final hemicatenane intermediate obtained once dHJs have converged. How binding of RMI1 to TopIIIα influences it to behave as a hemicatenane dissolvase, rather than as an enzyme that relaxes DNA topology, is unknown. Here, we present the crystal structure of human TopIIIα complexed to the first oligonucleotide-binding domain (OB fold) of RMI1. TopIII assumes a toroidal type 1A topoisomerase fold. RMI1 attaches to the edge of the gate in TopIIIα through which DNA passes. RMI1 projects a 23-residue loop into the TopIIIα gate, thereby influencing the dynamics of its opening and closing. Our results provide a mechanistic rationale for how RMI1 stabilizes TopIIIα-gate opening to enable dissolution and illustrate how binding partners modulate topoisomerase function.

AB - Repair of DNA double-strand breaks via homologous recombination can produce double Holliday junctions (dHJs) that require enzymatic separation. Topoisomerase IIIα (TopIIIα) together with RMI1 disentangles the final hemicatenane intermediate obtained once dHJs have converged. How binding of RMI1 to TopIIIα influences it to behave as a hemicatenane dissolvase, rather than as an enzyme that relaxes DNA topology, is unknown. Here, we present the crystal structure of human TopIIIα complexed to the first oligonucleotide-binding domain (OB fold) of RMI1. TopIII assumes a toroidal type 1A topoisomerase fold. RMI1 attaches to the edge of the gate in TopIIIα through which DNA passes. RMI1 projects a 23-residue loop into the TopIIIα gate, thereby influencing the dynamics of its opening and closing. Our results provide a mechanistic rationale for how RMI1 stabilizes TopIIIα-gate opening to enable dissolution and illustrate how binding partners modulate topoisomerase function.

KW - Amino Acid Sequence

KW - Binding Sites

KW - Carrier Proteins

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KW - Crystallography, X-Ray

KW - DNA Breaks, Double-Stranded

KW - DNA Topoisomerases, Type I

KW - DNA, Cruciform

KW - DNA, Single-Stranded

KW - Gene Deletion

KW - Humans

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Nuclear Proteins

KW - Oligonucleotides

KW - Saccharomyces cerevisiae

KW - Saccharomyces cerevisiae Proteins

KW - Sequence Homology, Amino Acid

KW - Solubility

U2 - 10.1038/nsmb.2775

DO - 10.1038/nsmb.2775

M3 - Journal article

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SN - 1545-9993

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EP - 268

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 3

ER -

Structural and mechanistic insight into Holliday-junction dissolution by topoisomerase IIIα and RMI1

Abstract

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