Proliferating cell nuclear antigen, cancer-associated isoform (caPCNA)

Proliferating cell nuclear antigen, cancer-associated isoform (caPCNA) is a post-translationally modified variant of the PCNA protein that is uniquely expressed in a broad range of cancer cells but absent in non-malignant tissues (Bechtel et al., 2006). It functions as a critical DNA clamp and scaffold, coordinating DNA replication, repair, and cell cycle progression by recruiting various proteins to the replication fork (Gu et al., 2023). Unlike the normal PCNA isoform, caPCNA possesses a structurally distinct interdomain connecting loop (IDCL), specifically in the L126-Y133 region, which serves as a selective binding pocket for therapeutic agents (Malkas et al., 2023). Drugs such as AOH1996 target this isoform to disrupt its interaction with RNA polymerase II and other replication factors, inducing lethal transcription-replication conflicts and DNA damage in malignant cells (Gu et al., 2023). This high degree of selectivity allows for the potential treatment of various solid tumors with minimal impact on healthy cells, addressing a major challenge in conventional chemotherapy (City of Hope, 2023). The presence of caPCNA in the serum and exosomes of cancer patients also makes it a valuable biomarker for early detection and monitoring of disease progression (Swaby, 2010; BioRxiv, 2025). Overall, caPCNA represents a novel and highly specific target for the development of broad-spectrum anti-cancer therapies.

Other names

Cancer-associated PCNAAcidic PCNA isoformcaPCNA

Selective inhibition of the cancer-associated isoform of PCNA by binding to the L126-Y133 region of the interdomain connecting loop, disrupting protein-protein interactions and inducing transcription-replication conflicts.