title: The E3 ubiquitin ligase Cullin 4A regulates meiotic progression in mouse spermatogenesis.
abstract: The Cullin-RING ubiquitin-ligase CRL4 controls cell cycle and DNA damage checkpoint response and ensures genomic integrity. Inactivation of the Cul4 component of the CRL4 E3 ligase complex in Caenorhabditis elegans by RNA interference results in massive mitotic DNA re-replication in the blast cells, largely due to failed degradation of the DNA licensing protein, CDT-1, and premature spermatogenesis. Here we show that inactivation of Cul4a by gene-targeting in mice only affected male but not female fertility. This male infertility phenotype resulted from a combination of decreased spermatozoa number, reduced sperm motility and defective acrosome formation. Agenesis of the mutant germ cells was accompanied by increased cell death in pachytene/diplotene cells with markedly elevated levels of phospho-p53 and CDT-1. Despite apparent normal assembly of synaptonemal complexes and DNA double strand break repair, dissociation of MLH1, a component of the late recombination nodule, was delayed in Cul4a -/- diplotene spermatocytes, which potentially led to subsequent disruptions in meiosis II and spermiogenesis. Together, our study revealed an indispensable role for Cul4a during male germ cell meiosis.
authors.affiliation: Division of Dermatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.forename: Congxing
authors.initials: C
authors.lastname: Lin
authors.forename: Sung Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Ignasi
authors.initials: I
authors.lastname: Roig
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Liren
authors.initials: L
authors.lastname: Liu
authors.forename: George Michael
authors.initials: GM
authors.lastname: Veith
authors.forename: Ramon U
authors.initials: RU
authors.lastname: Jin
authors.forename: Scott
authors.initials: S
authors.lastname: Keeney
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.forename: Kelle
authors.initials: K
authors.lastname: Moley
authors.forename: Pengbo
authors.initials: P
authors.lastname: Zhou
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
mesh_terms: D000177:Acrosome / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000235:genetics; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D013076:Sperm Count; D013081:Sperm Motility / Q000235:genetics; D013090:Spermatocytes / Q000166:cytology / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics*; D013573:Synaptonemal Complex / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016159:Tumor Suppressor Protein p53; D000070957:MutL Protein Homolog 1