Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave, Chicago, IL-60607, USA.
Dev Biol. 2011 Apr 15;352(2):278-87. doi: 10.1016/j.ydbio.2011.01.028. Epub 2011 Feb 1.
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.
哺乳动物的 Cul4 基因（Cul4A 和 Cul4B）编码基于 Cullin 的 E3 泛素连接酶的支架成分。这两个 Cul4 基因在功能上是冗余的。最近的研究表明，表达一种无法与其功能伙伴 ROC1 相互作用的截断 Cul4A 的小鼠没有表现出任何发育表型。我们生成了一种缺乏外显子 4-8 的 Cul4A-/- 品系，该品系不表达任何可检测到的截断蛋白。在这种品系中，雄性小鼠不育，并且精子发生严重缺乏。初级精母细胞在晚期前期 I 中缺乏进展，此时由于减数分裂性染色体失活，X 连锁的 Cul4B 基因的表达被沉默。Cul4A-/- 小鼠的睾丸表现出广泛的细胞凋亡。有趣的是，粗线期精母细胞表现出持续的双链断裂，表明同源重组的缺陷。此外，我们发现 CUL4A 定位于前期精母细胞中产生的双链断裂处。这些观察结果确定了 CUL4A 在减数重组中的新功能，并证明了 CUL4A 在精子发生中的重要作用。
