Derepression of Y-linked multicopy protamine-like genes interferes with sperm nuclear compaction in .

Across species, sperm maturation involves the dramatic reconfiguration of chromatin into highly compact nuclei that enhance hydrodynamic ability and ensure paternal genomic integrity. This process is mediated by the replacement of histones by sperm nuclear basic proteins, also referred to as protamines. In humans, a carefully balanced dosage between two known protamine genes is required for optimal fertility. However, it remains unknown how their proper balance is regulated and how defects in balance may lead to compromised fertility. Here, we show that a nucleolar protein, , a homolog of , mediates the histone-to-protamine transition during spermatogenesis. We find that mutants display nuclear compaction defects during late spermatogenesis due to decreased expression of autosomal protamine genes (including ) and derepression of Y-linked multicopy homologs (), leading to the mutant's known sterility. Overexpression of in a wild-type background is sufficient to cause nuclear compaction defects, similar to mutant, indicating that Mst77Y is a dominant-negative variant interfering with the process of histone-to-protamine transition. Interestingly, ectopic overexpression of caused decompaction of X-bearing spermatids nuclei more frequently than Y-bearing spermatid nuclei, although this did not greatly affect the sex ratio of offspring. We further show that regulates these protamine genes at the step of transcript polyadenylation. We conclude that the regulation of protamines mediated by , ensuring the expression of functional ones while repressing dominant-negative ones, is critical for male fertility.