The ubiquitin-conjugating yeast enzyme RAD6 and its human homologs hHR6A and hHR6B are implicated in postreplication repair and damage-induced mutagenesis. The yeast protein is also required for sporulation and may modulate chromatin structure via histone ubiquitination. We report the phenotype of the first animal mutant in the ubiquitin pathway: inactivation of the hHR6B-homologous gene in mice causes male infertility. Derailment of spermatogenesis becomes overt during the postmeiotic condensation of chromatin in spermatids. These findings provide a parallel between yeast sporulation and mammalian spermatogenesis and strongly implicate hHR6- dependent ubiquitination in chromatin remodeling. Since heterozygous male mice and even knockout female mice are completely normal and fertile and thus able to transmit the defect, similar hHR6B mutations may cause male infertility in man.
Bibliographical noteFunding Information:
The authors are indebted to Dr. G. Weeda and I. Donker for advice and instructions with the mouse embryo technology. Antibodies targeting TP2 were kindly provided by Dr. S. Kistler. Prepublished information concerning immunohistochemistry of tH2B was made available to us by Dr. M. Meistrich. We would like to thank Drs. S. Kistler and M. Meistrich for their valuable advice and discussions, M. Kuit for photographic work, and Dr. M. McKay for critically reading the manuscript. The work was supported by the Dutch Cancer Society (IKR 92–118 and 88–02), and the Division of Medical Sciences of the Dutch Scientific Organization (NWO, projects 900–501–093 and 903–44–138).