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doi: 10.1242/10.1242/jcs.00653


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Proliferating cell nuclear antigen (PCNA): a dancer with many partners

Giovanni Maga1 and Ulrich Hübscher2,*

1 DNA Enzymology and Molecular Virology, Istituto di Genetica Molecolare, IGM-CNR, National Research Council, via Abbiategrasso 207, I-27100 Pavia, Italy
2 Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland



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Fig. 1. Many PCNA partners share overlapping binding sites. The main regions of the PCNA ring involved in protein-protein interactions are highlighted along with the relevant partners. These are: (1) the interdomain connecting loop (aa L121 to E132; red); (2) the inner side {alpha}-helices at the N-terminus (pink); and (3) the C-terminal tail (blue). For clarity, only one region per each monomer is highlighted. The PCNA structure was generated with the program Swiss-PDBViewer from the PDB file 1AXC, rendered with QuickTime 3D and composed in Adobe PhotoShop.

 


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Fig. 2. A hypothetical model for the interplay between DNA polymerases involved in replication and translesion DNA synthesis. During DNA synthesis, the DNA replication machinery [schematically drawn as the pol {delta}/{epsilon} holoenzyme (pol {delta}/{epsilon}, RF-C, and PCNA)], eventually meets lesions on the DNA (represented with black symbols). Pol {delta} and {epsilon} are unable to traverse DNA lesions and their arrest causes the block of the replication fork. The current model predicts the existence of subnuclear compartments or foci (the `garages' in the drawing), where replicative or translesion (TLS) polymerases and their cognate auxiliary proteins are stored. When a replication fork stalls, checkpoints are activated leading to the recruitment of specific factors at the lesion through a yet unidentified machinery (drawn as an `auxiliary crane'). Consequently, replicative polymerases are lifted off and replaced by specialised TLS pols by a `polymerase crane'. After damage bypass, the normal replication machinery is reconstituted through an inverse mechanism. PCNA constitutes the common element to all these pathways, providing essential interactions with both replicative and TLS polymerases, as well as acting in the checkpoint process.

 


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Fig. 3. The interactions between PCNA and cell cycle regulatory networks. The eukaryotic cell cycle can be divided into the four phases: G1 (green), where cells grow in size, assess their metabolic status and get ready to divide; S (yellow), where the actual genome duplication takes place; G2 (green), where cells check for completion of DNA replication and prepare to divide and M (red), where mitosis and cytodieresis take place. Each phase is under the general control of specific CDK-cyclin complexes: the CDK4,6–cyclin-D complex regulates progression through G1, CDK2–cyclin-E is involved in regulating the transition from G1 to S phase (also known as the restriction point), CDK2–cyclin-A and CDK1–cyclin-A act throughout the S phase, whereas CDK1–Cyclin-B regulates mitosis. Moreover, specific checkpoint mechanisms can be activated halting the progression through the cell cycle in case problems arise. PCNA forms complexes with all these CDK–cyclin complexes as well as with critical checkpoint proteins, transducing both positive (indicated as arrows) and negative signals (indicated as T-bars).

 





© The Company of Biologists Ltd 2003