Discovering GCNA: A Novel Regulator of Germline Genomic Stability

Germ cells transfer genetic information across generations. Any change in germ line DNA is inherited by succeeding generations. Therefore, germ cell DNA must be protected from both internal and external assault. An advantage of sexual reproduction stems from the ability to generate variation by exchange of chromosomal segments during meiosis. During meiosis, hundreds of double-stranded DNA breaks are initiated at once, which if generated in most other cell types would introduce chromosomal aberrations. Germ cells, however, execute the formation of these breaks while preventing their deleterious effects from becoming pervasive throughout the genome. The mechanisms underlying the robustness of germ cells in the face of DNA damage, however, are poorly understood. We initiated an in vivo CRISPR-Cas9 knockout screen for genes highly enriched in the Drosophila female germ line. From this screen, we identified Germ Cell Nuclear Acidic Peptidase (GCNA) as a conserved regulator of genome stability across multiple species. Loss of GCNA results in replication stress, chromosomal instability, and an accumulation of DNA-protein crosslinks (DPCs). Disruption of GCNA leads to an accumulation of nuclear Top2 and Top2 DPCs. This work shows GCNA protects germ cells from damage and provides novel insights into the conserved networks that promote genome integrity across generations.

Author dc:creator

• Bhargava, Varsha

Contributors dc:contributor

• Mendell, Joshua T.
• Buszczak, Michael
• Olson, Eric N.
• Tu, Benjamin

• DNA Damage
• DNA Repair
• DNA Replication
• Fertility
• Genomic Instability
• Nuclear Proteins
• Peptide Hydrolases

Language dc:language

en

Identifier

1229059519

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/9299