Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
PLoS One. 2019 Jan 17;14(1):e0209995. doi: 10.1371/journal.pone.0209995. eCollection 2019.
Squamous cell carcinoma-related oncogene (SCCRO, also known as DCUN1D1) is a component of the E3 for neddylation. As such, DCUN1D1 regulates the neddylation of cullin family members. Targeted inactivation of DCUN1D1 in mice results in male-specific infertility. Infertility in DCUN1D1-/- mice is secondary to primary defects in spermatogenesis. Time-dam experiments mapped the onset of the defect in spermatogenesis to 5.5 to 6 weeks of age, which temporally corresponds to defects in spermiogenesis. Although the first round of spermatogenesis progressed normally, the number of spermatozoa released into the seminiferous lumen and epididymis of DCUN1D1-/- mice was significantly reduced. Spermatozoa in DCUN1D1-/- mice had multiple abnormalities, including globozoospermia, macrocephaly, and multiple flagella. Many of the malformed spermatozoa in DCUN1D1-/- mice were multinucleated, with supernumerary and malpositioned centrioles, suggesting a defect in the resolution of intercellular bridges. The onset of the defect in spermatogenesis in DCUN1D1-/- mice corresponds to an increase in DCUN1D1 expression observed during normal spermatogenesis. Moreover, consistent with its known function as a component of the E3 in neddylation, the pattern of DCUN1D1 expression temporally correlates with an increase in the neddylated cullin fraction and stage-specific increases in the total ubiquitinated protein pool in wild-type mice. Levels of neddylated Cul3 were decreased in DCUN1D1-/- mice, and ubiquitinated proteins did not accumulate during the stages in which DCUN1D1 expression peaks during spermatogenesis in wild-type mice. Combined, these findings suggest that DCUN1D1-/- mice fail to release mature spermatozoa into the seminiferous lumen, possibly due to unresolved intercellular bridges. Furthermore, the effects of DCUN1D1 on spermatogenesis likely involve its regulation of cullin-RING-ligase (CRL)-type ubiquitin E3 activity during spermiogenesis through its role in promoting Cul3 neddylation. The specific CRLs required for spermiogenesis and their protein targets require identification.
鳞状细胞癌相关癌基因（SCCRO，也称为 DCUN1D1）是泛素化 E3 的一个组成部分。因此，DCUN1D1 调节细胞周期蛋白家族成员的泛素化。在小鼠中靶向敲除 DCUN1D1 会导致雄性不育。DCUN1D1-/-小鼠的不育是由于精子发生的原发性缺陷引起的。时间损伤实验将精子发生缺陷的起始时间映射到 5.5 至 6 周龄，这与精子发生缺陷的时间相对应。尽管第一轮精子发生正常进行，但 DCUN1D1-/-小鼠释放到精囊管腔和附睾中的精子数量明显减少。DCUN1D1-/-小鼠的精子有多种异常，包括球形精子症、大头畸形和多个鞭毛。许多畸形精子的 DCUN1D1-/-小鼠是多核的，具有额外的和错位的中心粒，表明细胞间桥的分辨率存在缺陷。DCUN1D1-/-小鼠精子发生缺陷的起始时间与正常精子发生过程中观察到的 DCUN1D1 表达增加相对应。此外，与其作为泛素化 E3 的组成部分的已知功能一致，DCUN1D1 的表达模式与 neddylated Cul3 分数的增加以及野生型小鼠中总泛素化蛋白库的阶段特异性增加具有时间相关性。在 DCUN1D1-/-小鼠中，Cul3 的 neddylated 水平降低，并且在野生型小鼠精子发生过程中 DCUN1D1 表达达到峰值的阶段，泛素化蛋白没有积累。综合这些发现表明，DCUN1D1-/-小鼠不能将成熟精子释放到精囊管腔中，可能是由于细胞间桥未解决。此外，DCUN1D1 对精子发生的影响可能涉及通过促进 Cul3 neddylation 来调节其在精子发生过程中的细胞周期蛋白-RING 连接酶 (CRL)-型泛素 E3 活性。需要确定用于精子发生的特定 CRL 及其蛋白质靶标。
