Androgen insensivity chromatin negative nuclei

SUMO ligases, such as PIAS proteins, can assist SUMOylation by guiding the target lysine to the active site of the UBC9. SUMOs activated by SAE1/2 heterodimer are conjugated to target lysines by UBC9. The SUMOylation process is similar to ubiquitylation, but it requires a distinct enzymatic cascade. SUMO-1 is ~50% identical with SUMO-2 and -3 that are nearly identical (97%), and therefore often collectively referred to as SUMO-2/3 1, 4. 100-amino acid long proteins that possess the ubiquitin fold.

Mammalian cells possess three SUMO isoforms, SUMO-1, -2 and -3, that can be conjugated to proteins. SUMOylation functions by providing docking sites for interacting proteins, which leads to altered cellular localization, activity and/or stability of the target proteins. SUMO modifications have also been associated with many disease conditions, ranging from host antibacterial response, cardiovascular and neurodegenerative diseases to cancer 4, 5, 6, 7, 8. It has emerged as a widespread and important regulatory mechanism in cell physiology, especially in DNA damage, stress responses, nuclear signaling and in transcription 1, 2, 3, 4. SUMOylation, covalent conjugation of small ubiquitin-related modifiers (SUMOs), is a conserved posttranslational modification. Our studies thus indicate that epididymal AR SUMOylation is essential for the post-testicular sperm maturation and normal reproductive capability of male mice. AR is SUMOylated in the wild-type epididymis but not in the testis, which could explain the tissue-specific response to the lack of AR SUMOylation. Fittingly, their epididymal AR chromatin-binding and gene expression associated with sperm maturation and function are misregulated. Their spermatogenesis appears unaffected, but their epididymal sperm maturation is defective, shown by severely compromised motility and fertilization capacity of the sperm. ArKI males develop normally, without apparent defects in their systemic androgen action in reproductive tissues. Here, we generated a mouse model (ArKI) in which the conserved SUMO acceptor lysines of AR are permanently abolished ( Ar K381R, K500R). In vitro, the SUMOylation is linked to transcriptional repression and/or target gene-selective regulation. Androgen receptor (AR) is regulated by SUMOylation at its transactivation domain.

Androgen insensivity chromatin negative nuclei