Inhibition of filament formation of human Rad51 protein by a small peptide derived from the BRC-motif of the BRCA2 protein.
Human Rad51 is a key element of recombinational DNA repair and is related to the resistance of cancer cells to chemo- and radiotherapies. The protein is thus a potential target of anti-cancer treatment. The crystallographic analysis shows that the BRC-motif of the BRCA2 tumor suppressor is in contact with the subunit-subunit interface of Rad51 and could thus prevent filament formation of Rad51. However, biochemical analysis indicates that a BRC-motif peptide of 69 amino acids preferentially binds to the N-terminal part of Rad51. We show experimentally that a short peptide of 28 amino acids derived from the BRC4 motif binds to the subunit-subunit interface and dissociates its filament, both in the presence and absence of DNA, certainly by binding to dissociated monomers. The inhibition is efficient and specific for Rad51: the peptide does not even interact with Rad51 homologs or prevent their interaction with DNA. Neither the N-terminal nor the C-terminal half of the peptide interacts with human Rad51, indicating that both parts are involved in the interaction, as expected from the crystal structure. These results suggest the possibility of developing inhibitors of human Rad51 based on this peptide.
Nomme
Julian
J
UMR 6204, Centre National de la Recherche Scientifique, Université de Nantes, 44322 Nantes cedex 3, France.
Takizawa
Yoshimasa
Y
Martinez
Susan F
SF
Renodon-Cornière
Axelle
A
Fleury
Fabrice
F
Weigel
Pierre
P
Yamamoto
Ken-ichi
K
Kurumizaka
Hitoshi
H
Takahashi
Masayuki
M
D020816:Amino Acid Motifs; D051017:Apoptosis Regulatory Proteins; D024682:BRCA2 Protein / Q000737:chemistry* / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D010455:Peptides; D004247:DNA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase