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

    Research output: Contribution to journalArticle

    18 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

    Fingerprint

    Population
    Infertility
    Recombinases
    Mutation
    Schizosaccharomyces
    Homologous Recombination
    Meiosis
    Genetic Recombination
    Single Nucleotide Polymorphism
    Molecular Biology
    DNA
    Genes
    human DMC1 protein
    In Vitro Techniques

    ASJC Scopus subject areas

    • Genetics

    Cite this

    Hikiba, J., Hirota, K., Kagawa, W., Ikawa, S., Kinebuchi, T., Sakane, I., ... 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

    Structural and functional analyses of the DMC1-M200V polymorphism found in the human population. / Hikiba, Juri; Hirota, Kouji; Kagawa, Wataru; Ikawa, Shukuko; Kinebuchi, Takashi; Sakane, Isao; Takizawa, Yoshimasa; Yokoyama, Shigeyuki; Mandon-Pépin, Béatrice; Nicolas, Alain; Shibata, Takehiko; Ohta, Kunihiro; Kurumizaka, Hitoshi.

    In: Nucleic Acids Research, Vol. 36, No. 12, 07.2008, p. 4181-4190.

    Research output: Contribution to journalArticle

    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, vol. 36, no. 12, pp. 4181-4190. https://doi.org/10.1093/nar/gkn362
    Hikiba, Juri ; Hirota, Kouji ; Kagawa, Wataru ; Ikawa, Shukuko ; Kinebuchi, Takashi ; Sakane, Isao ; Takizawa, Yoshimasa ; Yokoyama, Shigeyuki ; Mandon-Pépin, Béatrice ; Nicolas, Alain ; Shibata, Takehiko ; Ohta, Kunihiro ; Kurumizaka, Hitoshi. / Structural and functional analyses of the DMC1-M200V polymorphism found in the human population. In: Nucleic Acids Research. 2008 ; Vol. 36, No. 12. pp. 4181-4190.
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