Roest H P, van Klaveren J, de Wit J, van Gurp C G, Koken M H, Vermey M, van Roijen J H, Hoogerbrugge J W, Vreeburg J T, Baarends W M, Bootsma D, Grootegoed J A, Hoeijmakers J H
MGC-Department of Cell Biology and Genetics, Faculty of Medicine and Health Sciences Erasmus University Rotterdam, The Netherlands.
Cell. 1996 Sep 6;86(5):799-810. doi: 10.1016/s0092-8674(00)80154-3.
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.
泛素结合酵母酶RAD6及其人类同源物hHR6A和hHR6B参与复制后修复和损伤诱导的诱变。酵母蛋白也是孢子形成所必需的，并且可能通过组蛋白泛素化调节染色质结构。我们报道了泛素途径中首个动物突变体的表型：小鼠中hHR6B同源基因的失活导致雄性不育。精子发生的紊乱在精子细胞减数分裂后染色质浓缩过程中变得明显。这些发现揭示了酵母孢子形成与哺乳动物精子发生之间的相似之处，并有力地表明hHR6依赖的泛素化参与染色质重塑。由于杂合雄性小鼠甚至基因敲除雌性小鼠完全正常且可育，因此能够传递该缺陷，类似的hHR6B突变可能导致人类男性不育。
