Abstract
SIRT6, the sixth member of the sirtuin family proteins, has been characterized as a crucial regulator in multiple molecular pathways related to aging, including genome stability, DNA damage repair, telomere maintenance, and inflammation. However, the exact roles of SIRT6 during female germ cell development have not yet been fully determined. Here, we assessed the acquisition of meiotic competency of porcine oocytes by inhibition of SIRT6 activity. We observed that SIRT6 inhibition led to the oocyte meiotic defects by showing the impairment of polar body extrusion and cumulus cell expansion. Meanwhile, the compromised spindle/chromosome structure and actin dynamics were also present in SIRT6-inhibited oocytes. Moreover, SIRT6 inhibition resulted in the defective cytoplasmic maturation by displaying the disturbed distribution dynamics of cortical granules and their content ovastacin. Notably, we identified that transcript levels of genes related to oocyte meiosis, oxidative phosphorylation, and cellular senescence were remarkably altered in SIRT6-inhibited oocytes by transcriptome analysis and validated that the meiotic defects caused by SIRT6 inhibition might result from the excessive reactive oxygen species (ROS)-induced early apoptosis in oocytes. Taken together, our findings demonstrate that SIRT6 promotes the porcine oocyte meiotic maturation through maintaining the redox homeostasis.
Highlights
During the meiotic maturation, mammalian fully grown oocytes at the prophase I stage undergo two key cellular events involving germinal vesicle breakdown and first polar body extrusion to reach the metaphase of the second meiosis (M II) stage awaiting for fertilization (Swann and Yu, 2008; Sun et al, 2009)
Quantitative results indicated that the rate of polar body extrusion (PBE) was decreased in a dose-dependent manner in SIRT6-inhibited oocytes in comparison with the controls
BubR1 was still present at kinetochores at metaphase I (M I) stage in SIRT6inhibited oocytes, indicative of persistent activation of spindle assembly checkpoint (SAC) (19.5% ± 2.8%, n = 36 vs. 48.5% ± 3.0%, n = 33, P < 0.001; Figures 1C,D)
Summary
Mammalian fully grown oocytes at the prophase I stage undergo two key cellular events involving germinal vesicle breakdown and first polar body extrusion to reach the metaphase of the second meiosis (M II) stage awaiting for fertilization (Swann and Yu, 2008; Sun et al, 2009). Sirtuin proteins (SIRT1–7) are a family of nicotinamide adenine dinucleotide (NAD+) enzymes that perform a diverse range of functions in the cells regarding energy metabolism, cellular stress resistance, genomic stability, and aging (Finkel et al, 2009). SIRT6 acts as a nuclear deacetylase and ADP-ribosyltransferase that participates in the telomere function, metabolic homeostasis, DNA repair, and genome stability (Kanfi et al, 2012; Toiber et al, 2013; Tian et al, 2019). SIRT6 is recruited to DNA double-strand breaks and associates with poly ADP-ribose polymerase 1 (PARP1) in the presence of DNA damage to activate the homologous and non-homologous end-joining recombination for damage repair (Morris, 2013; Pucci et al, 2013). The exact roles of SIRT6 in the female germ cells are not fully determined
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