title: Cul4A is essential for spermatogenesis and male fertility.
abstract: The mammalian Cul4 genes, Cul4A and Cul4B, encode the scaffold components of the cullin-based E3 ubiquitin ligases. The two Cul4 genes are functionally redundant. Recent study indicated that mice expressing a truncated CUL4A that fails to interact with its functional partner ROC1 exhibit no developmental phenotype. We generated a Cul4A-/- strain lacking exons 4-8 that does not express any detectable truncated protein. In this strain, the male mice are infertile and exhibit severe deficiencies in spermatogenesis. The primary spermatocytes are deficient in progression through late prophase I, a time point when expression of the X-linked Cul4B gene is silenced due to meiotic sex chromosome inactivation. Testes of the Cul4A-/- mice exhibit extensive apoptosis. Interestingly, the pachytene spermatocytes exhibit persistent double stranded breaks, suggesting a deficiency in homologous recombination. Also, we find that CUL4A localizes to the double stranded breaks generated in pre-pachytene spermatocytes. The observations identify a novel function of CUL4A in meiotic recombination and demonstrate an essential role of CUL4A in spermatogenesis.
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave, Chicago, IL-60607, USA.
authors.forename: Dragana
authors.initials: D
authors.lastname: Kopanja
authors.forename: Nilotpal
authors.initials: N
authors.lastname: Roy
authors.forename: Tanya
authors.initials: T
authors.lastname: Stoyanova
authors.forename: Rex A
authors.initials: RA
authors.lastname: Hess
authors.forename: Srilata
authors.initials: S
authors.lastname: Bagchi
authors.forename: Pradip
authors.initials: P
authors.lastname: Raychaudhuri
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D044842:Cullin Proteins / Q000235:genetics / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D005298:Fertility / Q000235:genetics / Q000502:physiology*; D008297:Male; D008540:Meiosis / Q000235:genetics / Q000502:physiology; D049469:Meiotic Prophase I / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011995:Recombination, Genetic; D013090:Spermatocytes / Q000166:cytology / Q000502:physiology; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology*; D013737:Testis / Q000002:abnormalities
chemical_list: C524851:Cul4B protein, mouse; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D017931:DNA Primers