Structural Insights into BCDX2 Complex Function in Homologous Recombination

Overview

Journal Nature

Specialty Science

Date 2023 Jun 21

PMID 37344589

Authors

Yashpal Rawal

Lijia Jia

Aviv Meir

Shuo Zhou

Hardeep Kaur

Eliza A Ruben

Youngho Kwon

Kara A Bernstein

Maria Jasin

Alexander B Taylor

Sandeep Burma

Robert Hromas

Alexander V Mazin

Weixing Zhao

Daohong Zhou

Elizabeth V Wasmuth

Eric C Greene

Patrick Sung

Shaun K Olsen

Affiliations

Soon will be listed here.

Abstract

Homologous recombination (HR) fulfils a pivotal role in the repair of DNA double-strand breaks and collapsed replication forks. HR depends on the products of several paralogues of RAD51, including the tetrameric complex of RAD51B, RAD51C, RAD51D and XRCC2 (BCDX2). BCDX2 functions as a mediator of nucleoprotein filament assembly by RAD51 and single-stranded DNA (ssDNA) during HR, but its mechanism remains undefined. Here we report cryogenic electron microscopy reconstructions of human BCDX2 in apo and ssDNA-bound states. The structures reveal how the amino-terminal domains of RAD51B, RAD51C and RAD51D participate in inter-subunit interactions that underpin complex formation and ssDNA-binding specificity. Single-molecule DNA curtain analysis yields insights into how BCDX2 enhances RAD51-ssDNA nucleoprotein filament assembly. Moreover, our cryogenic electron microscopy and functional analyses explain how RAD51C alterations found in patients with cancer inactivate DNA binding and the HR mediator activity of BCDX2. Our findings shed light on the role of BCDX2 in HR and provide a foundation for understanding how pathogenic alterations in BCDX2 impact genome repair.

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