PCNA: a silent housekeeper or a potential therapeutic target?

• PCNA coordinates the DNA replication machinery with key cellular functions.
• PCNA functions through multiple protein interaction and signaling modifications.
• Ubiquitylation and tyrosine phosphorylation fine-tune PCNA functions.
• Protein interaction and signaling pathways can be exploited to target PCNA.

Proliferating cell nuclear antigen (PCNA) is known as a molecular marker for proliferation given its role in replication. Three identical molecules of PCNA form a molecular sliding clamp around the DNA double helix. This provides an essential platform on which multiple proteins are dynamically recruited and coordinately regulated. Over the past decade, new research has provided a deeper comprehension of PCNA as a coordinator of essential cellular functions for cell growth, death, and maintenance. Although the biology of PCNA in proliferation has been comprehensively reviewed, research progress in unveiling the potential of targeting PCNA for disease treatment has not been systematically discussed. Here we briefly summarize the basic structural and functional characteristics of PCNA, and then discuss new developments in its protein interactions, trimer formation, and signaling regulation that open the door to possible therapeutic targeting of PCNA.