Protein arginine deiminase 6 (PAD6) is a homodimeric guanidine-modifying enzyme belonging to the amidinotransferase superfamily. It is a calcium-dependent enzyme that catalyzes the post-translational modification of target proteins by converting arginine to citrulline. PAD6 is expressed in mammalian oocytes, sperm cells, and early embryos. In mammalian oocytes and early embryo cytoplasm, its expression is localized to cytoskeletal sheets, dynamic structures containing various keratins, which are major targets for citrullination. PAD6-/- oocytes exhibit reduced microtubule acetylation and defective organelle positioning and redistribution, suggesting a role for PAD6 in regulating microtubule-mediated organelle movement and positioning. PAD6-/- female, but not male, mice are infertile due to a reduction of de novo protein synthesis, cytoskeletal sheet formation, and ribosomal RNA which induces arrest of zygote development at the two-cell stage. PAD6 is regulated by newborn ovary homeobox (Nobox), as its promoter contains a Nobox DNA-binding element (NBE) and expression and activity of PAD6 are decreased in Nobox-/- mouse ovaries.5 In human females, homozygous nonsense mutations and compound-heterozygous mutations in PAD6 induce early embryonic arrest following in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).
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