Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.
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.
Pellegrini
Luca
L
University of Cambridge, Department of Biochemistry, Tennis Court Road, Cambridge CB2 1GA, UK.
Yu
David S
DS
Lo
Thomas
T
Anand
Shubha
S
Lee
MiYoung
M
Blundell
Tom L
TL
Venkitaraman
Ashok R
AR
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D024682:BRCA2 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051135:Rad51 Recombinase; D011995:Recombination, Genetic; D020449:Repetitive Sequences, Amino Acid
D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; C495153:RAD51 protein, human; D051135:Rad51 Recombinase