GCNA is a histone binding protein required for spermatogonial stem cell maintenance

Abstract

Recycling and de-novo deposition of histones during DNA replication is a critical challenge faced by eukaryotic cells and is coordinated by histone chaperones. However, little is known about how tissue-specific histone chaperones function to maintain tissue homeostasis. Here we show that Germ Cell Nuclear Acidic protein (GCNA), a germ cell specific protein in adult mice, can bind histones and purified GCNA exhibits histone chaperone activity. GCNA associates with the DNA replication machinery and supports progression through S-phase in murine spermatogonial stem cells (SSCs). Whilst GCNA is dispensable for embryonic germ cell development, it is required for the maintenance of the SSC pool and for long-term production of sperm. Our work describes the role of a germ cell specific histone chaperone in SSCs maintenance in mice. These findings provide a mechanistic basis for the male infertility observed in patients carrying mutations in the GCNA locus.

ACRC/GCNA is an essential protease for the repair of DNA-protein crosslinks during vertebrate development

“…Interestingly, an ACRC conditional KO mouse model showed defects in spermatogenesis including dsDNA breaks and defective chromatin compaction, possibly via the TOP2 interaction, but a direct role of mouse Acrc in DPCR has not yet been identified. Instead, it has been proposed that mouse Acrc promotes genome integrity during meiosis by mediating protein-protein interactions via its IDR domain and its SUMO-interaction motifs 10 and by acting as a histone chaperone 29 . We show that Sprtn and Acrc are not redundant, considering that sprtn is endogenously expressed during the onset of lethality in ACRC mutants and the fact that injection of sprtn mRNA (Figure 3D) could not compensate for the lethality phenotype (Figure 6).…”

“…Interestingly, an ACRC conditional KO mouse model showed defects in spermatogenesis including dsDNA breaks and defective chromatin compaction, possibly via the TOP2 interaction, but a direct role of mouse Acrc in DPCR has not yet been identified. Instead, it has been proposed that mouse Acrc promotes genome integrity during meiosis by mediating protein-protein interactions via its IDR domain and its SUMO-interaction motifs 10 and by acting as a histone chaperone 29 .…”