Structural and functional analyses of the DMC1-M200V polymorphism found in the human population

Juri Hikiba, Kouji Hirota, Wataru Kagawa, Shukuko Ikawa, Takashi Kinebuchi, Isao Sakane, Yoshimasa Takizawa, Shigeyuki Yokoyama, Béatrice Mandon-Pépin, Alain Nicolas, Takehiko Shibata, Kunihiro Ohta, Hitoshi Kurumizaka

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    19 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)4181-4190
    Number of pages10
    JournalNucleic Acids Research
    Volume36
    Issue number12
    DOIs
    Publication statusPublished - 2008 Jul

    ASJC Scopus subject areas

    • Genetics

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  • Cite this

    Hikiba, J., Hirota, K., Kagawa, W., Ikawa, S., Kinebuchi, T., Sakane, I., Takizawa, Y., Yokoyama, S., Mandon-Pépin, B., Nicolas, A., Shibata, T., Ohta, K., & Kurumizaka, H. (2008). Structural and functional analyses of the DMC1-M200V polymorphism found in the human population. Nucleic Acids Research, 36(12), 4181-4190. https://doi.org/10.1093/nar/gkn362