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

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.

• Authors: 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
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 36 Issue 12 Pg. 4181-90 (Jul 2008) ISSN: 1362-4962 [Electronic] England
• PMID: 18566005 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA-Binding Proteins
• Dmc1 protein, S pombe
• Recombinases
• Schizosaccharomyces pombe Proteins
• DNA
• Arginine
• DMC1 protein, human

Topics

• Amino Acid Sequence
• Arginine (chemistry)
• Cell Cycle Proteins (chemistry, genetics, metabolism)
• Chromosome Pairing
• Crystallography, X-Ray
• DNA (metabolism)
• DNA-Binding Proteins (chemistry, genetics, metabolism)
• Humans
• Meiosis (genetics)
• Molecular Sequence Data
• Polymorphism, Single Nucleotide
• Recombinases (genetics)
• Recombination, Genetic
• Schizosaccharomyces pombe Proteins (genetics)