Structural and functional analyses of the DMC1-M200V polymorphism found in the human population.
The M200V polymorphism of the human DMC1 protein, which is an essential, meiosis-specific DNA recombinase, was found in an infertile patient, raising the question of whether this homozygous human DMC1-M200V polymorphism may cause infertility by affecting the function of the human DMC1 protein. In the present study, we determined the crystal structure of the human DMC1-M200V variant in the octameric-ring form. Biochemical analyses revealed that the human DMC1-M200V variant had reduced stability, and was moderately defective in catalyzing in vitro recombination reactions. The corresponding M194V mutation introduced in the Schizosaccharomyces pombe dmc1 gene caused a significant decrease in the meiotic homologous recombination frequency. Together, these structural, biochemical and genetic results provide extensive evidence that the human DMC1-M200V mutation impairs its function, supporting the previous interpretation that this single-nucleotide polymorphism is a source of human infertility.
Hikiba
Juri
J
Laboratory of Structural Biology, Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
Hirota
Kouji
K
Kagawa
Wataru
W
Ikawa
Shukuko
S
Kinebuchi
Takashi
T
Sakane
Isao
I
Takizawa
Yoshimasa
Y
Yokoyama
Shigeyuki
S
Mandon-Pépin
Béatrice
B
Nicolas
Alain
A
Shibata
Takehiko
T
Ohta
Kunihiro
K
Kurumizaka
Hitoshi
H
D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D023902:Chromosome Pairing; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008540:Meiosis / Q000235:genetics; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D045522:Recombinases / Q000235:genetics; D011995:Recombination, Genetic; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C514358:Dmc1 protein, S pombe; D045522:Recombinases; D029702:Schizosaccharomyces pombe Proteins; D004247:DNA; D001120:Arginine; C074556:DMC1 protein, human