Proliferating cell nuclear antigen (PCNA) (PCNA)

Proliferating cell nuclear antigen (PCNA) is a highly conserved homotrimeric protein that functions as a DNA sliding clamp and a central scaffold for proteins involved in DNA synthesis and repair (UniProt P12004). While many proteins interact with PCNA via the PIP-box motif, a distinct set of proteins involved in the cellular stress response interact via the APIM (AlkB homolog 2 PCNA-interacting motif) (Gilljam et al., 2009). APIM-dependent protein complexes are crucial for coordinating DNA repair and survival signaling when cells are under genotoxic stress. Targeting these specific interactions, particularly with APIM-mimetic peptides like ATX-101, aims to selectively disrupt the stress-handling capacity of cancer cells. This approach sensitizes tumors to conventional chemotherapy and radiotherapy by preventing the recruitment of repair enzymes to damaged DNA (Slupphaug et al., 2022). Because APIM-mediated interactions are more prominent during stress than during normal replication, this strategy offers a potentially wider therapeutic window compared to broad PCNA inhibitors.

Other names

CyclinDNA polymerase delta auxiliary proteinAPIM-PCNA complexPCNA-APIM interaction

Competitive inhibition of APIM-mediated protein-protein interactions on the PCNA scaffold, which disrupts the recruitment of DNA repair and stress-response proteins, thereby sensitizing cells to genotoxic stress (Müller et al., 2013).