Cited by 704DNA Repair MechanismsBRCA gene mutations in cancerPARP inhibition in cancer therapy

Insights into DNA recombination from the structure of a RAD51–BRCA2 complex

Pellegrini, Luca, Yu, David S., Lo, Thomas, Anand, Shubha, Lee, MiYoung, Blundell, Tom L., Venkitaraman, Ashok R.·2002·Nature

Abstract

The breast cancer susceptibility protein BRCA2 controls the function of RAD51, a recombinase enzyme, in pathways for DNA repair by homologous recombination. We report here the structure of a complex between an evolutionarily conserved sequence in BRCA2 (the BRC repeat) and the RecA-homology domain of RAD51. The BRC repeat mimics a motif in RAD51 that serves as an interface for oligomerization between individual RAD51 monomers, thus enabling BRCA2 to control the assembly of the RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. The RAD51 oligomerization motif is highly conserved among RecA-like recombinases, highlighting a common evolutionary origin for the mechanism of nucleoprotein filament formation, mirrored in the BRC repeat. Cancer-associated mutations that affect the BRC repeat disrupt its predicted interaction with RAD51, yielding structural insight into mechanisms for cancer susceptibility.

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Crossref · 10.1038/nature01230

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  • H-bond staples are not unique to MAPKAPK docking regions bound to MAPKs and are also used in other linear motif based interaction systems such as TGFβ signaling and DNA repair regulation.

    “H-bond staples, however, are not unique to MAPKAPK docking regions bound to MAPKs and are also used in other linear motif based interaction systems such as those operating in TGFβ signaling (the TGFβ effector SMAD3 interacts with a linear motif in the adaptor SARA) or in DNA repair regulation (the DNA recombinase RAD51 interacts with a short peptide segment from the scaffold protein BRCA2 ) (39-41”
  • RAD51's core domain, T3, binds BRCA1-BARD1, but not the BRCA1-BARD11-142 or BRCA11-500-BARD1 complexes.

    “the core domain of RAD51 (referred to as T3), which has been implicated in BRCA2 binding via the BRC4 repeat of the latter41, is able to interact with BRCA1-BARD1 (Extended Data Fig. 3f), but not with BRCA1-BARD11-142 or BRCA11-500-BARD1”

    From BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing (2017) · cites this paper as [41]

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Authors
Pellegrini, L., Yu, D. S., Lo, T., Anand, S., Lee, M., Blundell, T. L., & Venkitaraman, A. R.
Affiliations
University of Cambridge (GB)
Corresponding author
Venkitaraman, Ashok R.
Venue
Nature
Published
2002-11
Volume
420
Issue
6913
Pages
287-293
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2140036600
Cited by
704
References
36
Citations by year
2026: 18 · 2025: 27 · 2024: 20 · 2023: 29 · 2022: 18 · 2021: 34 · 2020: 27 · 2019: 23 · 2018: 26 · 2017: 26 · 2016: 35 · 2015: 24 · 2014: 36 · 2013: 29 · 2012: 30
FWCI
12.40
Type
journal article
Language
en
Open access
closed
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords
BRCA2, RAD51, BRC repeats, homologous recombination, DNA repair, protein complex structure, breast cancer
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Breast Neoplasms, DNA-Binding Proteins, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Protein Binding, Recombination, Genetic, Conserved Sequence, Protein Structure, Tertiary, Crystallography, X-Ray, Genetic Predisposition to Disease, Repetitive Sequences, Amino Acid, Amino Acid Motifs, BRCA2 Protein, Macromolecular Substances, Rad51 Recombinase, Hydrophobic and Hydrophilic Interactions

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