GCNA Interacts with Spartan and Topoisomerase II to Regulate Genome Stability

Abstract

GCNA proteins are expressed across eukarya in pluripotent cells and have conserved functions in fertility. GCNA homologs Spartan (DVC-1) and Wss1 resolve DNA-protein crosslinks (DPCs), including Topoisomerase-DNA adducts, during DNA replication. Here, we show that GCNA mutants in mouse and C. elegans display defects in genome maintenance including DNA damage, aberrant chromosome condensation, and crossover defects in mouse spermatocytes and spontaneous genomic rearrangements in C. elegans. We show that GCNA and topoisomerase II (TOP2) physically interact in both mice and worms and colocalize on condensed chromosomes during mitosis in C. elegans embryos. Moreover, C. elegans gcna-1 mutants are hypersensitive to TOP2 poison. Together, our findings support a model in which GCNA provides genome maintenance functions in the germline and may do so, in part, by promoting the resolution of TOP2 DPCs. DNA topoisomerases help unwind DNA but occasionally get trapped, resulting in DNA-protein crosslinks (DPCs). DPCs damage DNA and threaten genomic integrity. Dokshin et al. find that GCNA protein family complements standard DPC processing machinery in resolving topoisomerase II DPCs to ensure heritable genome stability and germline immortality.