PCNA's dual legacy in ciliates: Conserved replication scaffold and lineage-specific genome architect

Proliferating cell nuclear antigen (PCNA) is a central scaffold in eukaryotic DNA replication, repair, and epigenetic regulation. While its roles are well-characterized in canonical model organisms, ciliates, unicellular eukaryotes with nuclear dimorphism and programmed genome remodeling, offer unparalleled insights into PCNA's functional adaptability. Their unique biology, including replication-coupled DNA elimination, macronuclear amplification, and replication band dynamics, positions PCNA at the intersection of genome stability and plasticity. This review systematically compares ciliate and human PCNA through phylogenetic, structural, and functional analyses. We reveal that ciliate PCNAs, despite ∼50 % sequence divergence from mammals, preserve conserved trimerization interfaces and partner-binding motifs, as validated by AlphaFold3-predicted models of the classical model organism Tetrahymena thermophila and the emerging systems Euplotes eurystomus and Stylonychia lemnae. Functional summaries highlight lineage-specific innovations, including epigenetic regulation, paralog specialization for nuclear differentiation, and replication band assembly. These findings have broader implications for elucidating replication-coupled chromatin dynamics, the adaptive evolution of multiprotein complexes, and the use of non-model organisms such as E. eurystomus and S. lemnae to uncover conserved principles of genome biology.