INACTIVATION OF THE HR6B UBIQUITIN-CONJUGATING DNA-REPAIR ENZYME IN MICE CAUSES MALE-STERILITY ASSOCIATED WITH CHROMATIN MODIFICATION

The ubiquitin-conjugating yeast enzyme RAD6 and its human homologs hHR 6A and hHR6B are implicated in postreplication repair and damage-induc ed mutagenesis, The yeast protein is also required for sporulation and may modulate chromatin structure via histone ubiquitination. We repor t the phenotype of the first animal mutant in the ubiquitin pathway: i nactivation of the hHR6B-homologous gene in mice causes male infertili ty. Derailment of spermatogenesis becomes overt during the postmeiotic condensation of chromatin in spermatids. These findings provide a par allel between yeast sporulation and mammalian spermatogenesis and stro ngly implicate hHR6-dependent ubiquitination in chromatin remodeling. Since heterozygous male mice and even knockout female mice are complet ely normal and fertile and thus able to transmit the defect, similar h HR6B mutations may cause male infertility in man.