MEILB2-BRME1 forms a V-shaped DNA clamp upon BRCA2-binding in meiotic recombination

Gurusaran Manickam; Jingjing Zhang; Kexin Zhang; Hiroki Shibuya; Owen Davies

doi:10.1038/s41467-024-50920-x

MEILB2-BRME1 forms a V-shaped DNA clamp upon BRCA2-binding in meiotic recombination

Gurusaran Manickam, Jingjing Zhang, Kexin Zhang, Hiroki Shibuya, Owen Davies

School of Biological Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

DNA double-strand break repair by homologous recombination has a specialised role in meiosis by generating crossovers that enable the formation of haploid germ cells. This requires meiosis-specific MEILB2-BRME1, which interacts with BRCA2 to facilitate loading of recombinases onto resected DNA ends. Here, we report the crystal structure of the MEILB2-BRME1 2:2 core complex, revealing a parallel four-helical assembly that recruits BRME1 to meiotic double-strand breaks in vivo. It forms an N-terminal β-cap that binds to DNA, and a MEILB2 coiled-coil that bridges to C-terminal ARM domains. Upon BRCA2-binding, MEILB2-BRME1 2:2 complexes dimerize into a V-shaped 2:4:4 complex, with rod-like MEILB2-BRME1 components arranged at right-angles. The β-caps located at the tips of the MEILB2-BRME1 limbs are separated by 25 nm, allowing them to bridge between DNA molecules. Thus, we propose that BRCA2 induces MEILB2-BRME1 to function as a DNA clamp, connecting resected DNA ends or homologous chromosomes to facilitate meiotic recombination.

Original language	English
Article number	6552
Number of pages	16
Journal	Nature Communications
Volume	15
DOIs	https://doi.org/10.1038/s41467-024-50920-x
Publication status	Published - 2 Aug 2024

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s41467-024-50920-xFinal published version, 3.87 MBLicence: Creative Commons: Attribution (CC-BY)

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The Hidden Cell Discovery Research Platform
Marston, A. (Principal Investigator), Allshire, R. (Co-investigator), Davies, O. (Co-investigator), El Karoui, M. (Co-investigator), Kustatscher, G. (Co-investigator), O'Carroll, D. (Co-investigator), Rappsilber, J. (Co-investigator) & Rosser, S. (Co-investigator)
Wellcome Trust (Rcl)
1/12/23 → 30/11/30
Project: Research
Molecular basis of chromosome synapsis and genetic exchange in mammalian meiosis
Davies, O. (Principal Investigator)
UK-based charities
15/02/21 → 14/02/26
Project: Research
Purchase of a high-resolution electron cryo-microscope
Böttcher, B. (Principal Investigator), Earnshaw, B. (Co-investigator), Kohl, A. (Co-investigator), SPAGNOLO, L. (Co-investigator) & Walkinshaw, M. (Co-investigator)
UK-based charities
1/08/09 → 31/07/14
Project: Research

Cite this

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title = "MEILB2-BRME1 forms a V-shaped DNA clamp upon BRCA2-binding in meiotic recombination",

abstract = "DNA double-strand break repair by homologous recombination has a specialised role in meiosis by generating crossovers that enable the formation of haploid germ cells. This requires meiosis-specific MEILB2-BRME1, which interacts with BRCA2 to facilitate loading of recombinases onto resected DNA ends. Here, we report the crystal structure of the MEILB2-BRME1 2:2 core complex, revealing a parallel four-helical assembly that recruits BRME1 to meiotic double-strand breaks in vivo. It forms an N-terminal β-cap that binds to DNA, and a MEILB2 coiled-coil that bridges to C-terminal ARM domains. Upon BRCA2-binding, MEILB2-BRME1 2:2 complexes dimerize into a V-shaped 2:4:4 complex, with rod-like MEILB2-BRME1 components arranged at right-angles. The β-caps located at the tips of the MEILB2-BRME1 limbs are separated by 25 nm, allowing them to bridge between DNA molecules. Thus, we propose that BRCA2 induces MEILB2-BRME1 to function as a DNA clamp, connecting resected DNA ends or homologous chromosomes to facilitate meiotic recombination. ",

author = "Gurusaran Manickam and Jingjing Zhang and Kexin Zhang and Hiroki Shibuya and Owen Davies",

note = "We thank Diamond Light Source and the staff of beamlines I04 and B21 (proposal mx25233), the cryo-EM facility in the School of Biological Sciences at the University of Edinburgh (SULSA and Wellcome Grant 087658/Z/08/Z) and the Atomic Force Microscopy Facility in the School of Engineering at the University of Edinburgh. This work was supported by a Wellcome Senior Research Fellowship 219413/Z/19/Z (O.R.D.), a core grant to the Wellcome Centre for Cell Biology 203149 (O.R.D.), the Structural Biology core of the Wellcome Discovery Research Platform for Hidden Cell Biology 226791 (O.R.D.), and the European Research Council StG-801659 (H.S.). ",

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doi = "10.1038/s41467-024-50920-x",

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AU - Shibuya, Hiroki

AU - Davies, Owen

N1 - We thank Diamond Light Source and the staff of beamlines I04 and B21 (proposal mx25233), the cryo-EM facility in the School of Biological Sciences at the University of Edinburgh (SULSA and Wellcome Grant 087658/Z/08/Z) and the Atomic Force Microscopy Facility in the School of Engineering at the University of Edinburgh. This work was supported by a Wellcome Senior Research Fellowship 219413/Z/19/Z (O.R.D.), a core grant to the Wellcome Centre for Cell Biology 203149 (O.R.D.), the Structural Biology core of the Wellcome Discovery Research Platform for Hidden Cell Biology 226791 (O.R.D.), and the European Research Council StG-801659 (H.S.).

PY - 2024/8/2

Y1 - 2024/8/2

N2 - DNA double-strand break repair by homologous recombination has a specialised role in meiosis by generating crossovers that enable the formation of haploid germ cells. This requires meiosis-specific MEILB2-BRME1, which interacts with BRCA2 to facilitate loading of recombinases onto resected DNA ends. Here, we report the crystal structure of the MEILB2-BRME1 2:2 core complex, revealing a parallel four-helical assembly that recruits BRME1 to meiotic double-strand breaks in vivo. It forms an N-terminal β-cap that binds to DNA, and a MEILB2 coiled-coil that bridges to C-terminal ARM domains. Upon BRCA2-binding, MEILB2-BRME1 2:2 complexes dimerize into a V-shaped 2:4:4 complex, with rod-like MEILB2-BRME1 components arranged at right-angles. The β-caps located at the tips of the MEILB2-BRME1 limbs are separated by 25 nm, allowing them to bridge between DNA molecules. Thus, we propose that BRCA2 induces MEILB2-BRME1 to function as a DNA clamp, connecting resected DNA ends or homologous chromosomes to facilitate meiotic recombination.

AB - DNA double-strand break repair by homologous recombination has a specialised role in meiosis by generating crossovers that enable the formation of haploid germ cells. This requires meiosis-specific MEILB2-BRME1, which interacts with BRCA2 to facilitate loading of recombinases onto resected DNA ends. Here, we report the crystal structure of the MEILB2-BRME1 2:2 core complex, revealing a parallel four-helical assembly that recruits BRME1 to meiotic double-strand breaks in vivo. It forms an N-terminal β-cap that binds to DNA, and a MEILB2 coiled-coil that bridges to C-terminal ARM domains. Upon BRCA2-binding, MEILB2-BRME1 2:2 complexes dimerize into a V-shaped 2:4:4 complex, with rod-like MEILB2-BRME1 components arranged at right-angles. The β-caps located at the tips of the MEILB2-BRME1 limbs are separated by 25 nm, allowing them to bridge between DNA molecules. Thus, we propose that BRCA2 induces MEILB2-BRME1 to function as a DNA clamp, connecting resected DNA ends or homologous chromosomes to facilitate meiotic recombination.

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DO - 10.1038/s41467-024-50920-x

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 6552

ER -

MEILB2-BRME1 forms a V-shaped DNA clamp upon BRCA2-binding in meiotic recombination

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Projects

The Hidden Cell Discovery Research Platform

Molecular basis of chromosome synapsis and genetic exchange in mammalian meiosis

Purchase of a high-resolution electron cryo-microscope

Cite this