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 Citations (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.

Original language	English
Journal	Nature Structural and Molecular Biology
Volume	21
Issue number	3
Pages (from-to)	261-8
Number of pages	8
ISSN	1545-9993
DOIs	https://doi.org/10.1038/nsmb.2775
Publication status	Published - Mar 2014

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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title = "Structural and mechanistic insight into Holliday-junction dissolution by topoisomerase IIIα and RMI1",

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.",

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author = "Nicolas Bocquet and Bizard, {Anna H} and Wassim Abdulrahman and Larsen, {Nicolai B} and Mahamadou Faty and Simone Cavadini and Bunker, {Richard D} and Kowalczykowski, {Stephen C} and Petr Cejka and Hickson, {Ian D} and Thom{\"a}, {Nicolas H}",

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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

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KW - Crystallography, X-Ray

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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

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U2 - 10.1038/nsmb.2775

DO - 10.1038/nsmb.2775

M3 - Journal article

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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

Keywords

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