Proliferating cell nuclear antigen

Cryo-EM structure of the DNA-bound PolD–PCNA processive complex

Proliferating Cell Nuclear Antigen (PCNA) is a protein that plays a crucial role in DNA replication and DNA repair mechanisms within a cell. It acts as a processivity factor for DNA polymerase δ in eukaryotic cells, essentially encircling the DNA strand to increase the enzyme's ability to synthesize DNA efficiently. PCNA is a homotrimer, meaning it is composed of three identical subunits, which form a ring-shaped structure that can slide along the DNA strand.

Function

PCNA's primary function is to increase the DNA polymerase's processivity, allowing for the rapid and efficient synthesis of DNA. This is crucial during the S phase of the cell cycle, where DNA replication occurs. Besides its role in DNA synthesis, PCNA is involved in DNA repair processes, cell cycle regulation, and chromatin assembly. It interacts with various proteins and serves as a platform for the assembly of protein complexes involved in these processes.

DNA Replication

During DNA replication, PCNA is loaded onto the DNA at the replication fork by the replication factor C (RFC) complex. Once loaded, it recruits DNA polymerase δ, enhancing its processivity. This interaction is vital for the synthesis of the lagging strand during replication.

DNA Repair

PCNA is also involved in several DNA repair pathways, including nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR). It recruits and interacts with various repair proteins at sites of DNA damage, facilitating the repair process.

Cell Cycle Regulation

PCNA plays a role in cell cycle regulation by interacting with proteins involved in cell cycle control. Its levels are tightly regulated throughout the cell cycle, peaking during the S phase.

Clinical Significance

Given its central role in DNA replication and repair, PCNA is a marker for cell proliferation. Elevated levels of PCNA are often observed in actively dividing cells, including cancer cells. As such, PCNA can be used as a prognostic marker in various cancers, indicating the aggressiveness of the tumor based on the level of cell proliferation.

Structure

The PCNA protein is a homotrimer, with each monomer consisting of two similar domains that form a ring structure. This ring encircles the DNA, sliding along it during the replication process. The structure of PCNA allows it to interact with a wide range of proteins, facilitated by various PCNA-interacting protein (PIP) boxes and other interaction motifs.

Research and Applications

Research on PCNA continues to uncover its roles in DNA replication, repair, and cell cycle regulation. Understanding PCNA's interactions and functions at a molecular level can lead to the development of targeted therapies, especially in cancer treatment, where modulating DNA repair and cell proliferation pathways could be beneficial.