CRL4 complex regulates mammalian oocyte survival and reprogramming by activation of TET proteins

Science. 2013 Dec 20;342(6165):1518-21. doi: 10.1126/science.1244587.


The duration of a woman's reproductive period is determined by the size and persistence of a dormant oocyte pool. Specific oocyte genes are essential for follicle maintenance and female fertility. The mechanisms that regulate the expression of these genes are poorly understood. We found that a cullin-ring finger ligase-4 (CRL4) complex was crucial in this process. Oocyte-specific deletion of the CRL4 linker protein DDB1 or its substrate adaptor VPRBP (also known as DCAF1) caused rapid oocyte loss, premature ovarian insufficiency, and silencing of fertility maintaining genes. CRL4(VPRBP) activates the TET methylcytosine dioxygenases, which are involved in female germ cell development and zygote genome reprogramming. Hence, CRL4(VPRBP) ubiquitin ligase is a guardian of female reproductive life in germ cells and a maternal reprogramming factor after fertilization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Cellular Reprogramming / genetics*
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases / genetics
  • Dioxygenases / metabolism*
  • Female
  • Fertility / genetics*
  • Gene Silencing
  • Gonadal Dysgenesis / genetics
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Mixed Function Oxygenases
  • Oocytes / physiology*
  • Ovary / physiopathology
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*


  • Carrier Proteins
  • Cul4B protein, mouse
  • Cul4a protein, mouse
  • Cullin Proteins
  • DNA-Binding Proteins
  • Ddb1 protein, mouse
  • Proto-Oncogene Proteins
  • RBX1 protein, mouse
  • Mixed Function Oxygenases
  • TET1 protein, human
  • TET3 protein, human
  • Dioxygenases
  • TET2 protein, human
  • Protein Serine-Threonine Kinases
  • VprBP protein, mouse