8UVW

Crystal structure of RAD51-BRCA2 Cter complex

Summary for 8UVW

• Entry DOI: 10.2210/pdb8uvw/pdb
• Descriptor: Breast cancer type 2 susceptibility protein, DNA repair protein RAD51 homolog 1 fusion, DNA repair protein RAD51 homolog 1,Breast cancer type 2 susceptibility protein, ADENOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: homologous recombination, dna repair, dsb repair, recombination
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 64538.52

Authors

Longo, M.A.,Perera, R.,Tsai, C.-L.,Tainer, J.A. (deposition date: 2023-11-05, release date: 2024-11-06, Last modification date: 2025-10-01)

Primary citation

Longo, M.A.,Ahmed, S.M.,Chen, Y.,Tsai, C.L.,Namjoshi, S.,Shen, R.,Ahmed, Z.,Wang, X.,Perera, R.L.,Arvai, A.,Lee, M.,Kong, L.R.,Engl, W.,Ng, W.S.,Zhao, Z.W.,Venkitaraman, A.R.,Tainer, J.A.,Schlacher, K.
BRCA2 C-terminal clamp restructures RAD51 dimers to bind B-DNA for replication fork stability.
Mol.Cell, 85:2080-2096.e6, 2025

PubMed Abstract: Tumor suppressor protein breast cancer susceptibility protein 2 (BRCA2) acts with RAD51 in replication fork protection (FP) and homology-directed DNA-break repair (HDR). Critical for cancer etiology and therapy resistance, the BRCA2 C terminus was thought to stabilize recombinogenic RAD51 after the assembly of ATP-extended RAD51 filaments on single-stranded DNA (ssDNA). Here, the detailed crystal structure of the human BRCA2 C-terminal interaction domain (TR2 interface [TR2i]) complexed with ATP-bound RAD51 prior to DNA binding instead reveals TR2i unexpectedly induces a unique ATP-RAD51 dimer conformation that accommodates nucleation onto double-stranded B-DNA unsuited for HDR initiation. Structural, biochemical, and molecular results with interface-guided mutations uncover TR2i's FP mechanism. Proline-driven secondary structure stabilizes residue triads and spans the RAD51 dimer, engaging pivotal interactions of RAD51 M210 and BRCA2 S3291/P3292, the cyclin-dependent kinase (CDK) phosphorylation site that toggles between FP during S phase and HDR in G2. TR2i evidently acts as an allosteric clamp, switching RAD51 from ssDNA to double-stranded and B-DNA binding, enforcing FP over HDR, challenging the current BRCA2-RAD51 dogma.

PubMed: 40441151
DOI: 10.1016/j.molcel.2025.05.010

Experimental method

X-RAY DIFFRACTION (2.73 Å)