Proliferating cell nuclear antigen function

One fascinating observation is that PCNA (proliferating cell nuclear antigen) can be modified by multiple forms of ubiquitin, demonstrating that DUBs with different specificities can act at the same location on a specific substrate. PCNA can be modified by mono-ubiquitin, 63-linked polyubiquitin, or SUMO at K164 [89]. Modification of PCNA by mono- or polyubiquitin determines whether it is utilized in translesion synthesis or error-free DNA repair, respectively. SUMO modification prevents PCNA function in DNA repair and instead promotes DNA replication. It is probable that multiple DUBs, as yet unidentified, are required to regulate PCNA modification. 

Jonsson Z, Podust V, Podust L, Hubscher U (1995) Tyrosine 114 is essential for the trimeric structure and the functional activities of human proliferating cell nuclear antigen. EMBO J 14 5745-5751... 

Both Rtel and dog-1 encode proteins which contain a conserved helicase motif as well as a domain for interaction with proliferating cell nuclear antigen (PCNA), part of the replication apparatus. This suggests that these proteins may function by unwinding G4 DNA that could otherwise impair replication. Biochemical analysis of the activities of RTEL, DOG-1, and related factors should prove very interesting. 

It may be the principal leading strand polymerase. Requires a protein called proliferating cell nuclear antigen (PCNA) to carry out highly processive DNA synthesis in vitro. PCNA functions like the clamp of E. coli DNA Polymerase III holoenzyme. 

Polymerase a was the first discovered, and it has the most subunits. It also has the ability to make primers, but it lacks a 3 5 proofreading activity and has low processivity. After making the RNA primer, Pol a adds about 20 nucleotides and is then replaced by Pol 5 and e. Polymerase 5 is the principal DNA polymerase in eukaryotes. It interacts with a special protein called PCNA ior proliferating cell nuclear antigen). PCNA is the eukaryotic equivalent of the part of Pol III that functions as a sliding clamp (P). It is a trimer of three identical proteins that surround the DNA (Figure 10.19). The role of DNA polymerase e is less clear. It may replace polymerase 5 in lagging strand synthesis. DNA polymerase p appears to be a repair enzyme. DNA polymerase y carries out DNA replication in mitochondria. Several... 

Chang, D. Y, and Lu, A. L. (2002). Functional interaction of MutY homolog with proliferating cell nuclear antigen in fission yeast, Schizosaccharomyces pombe. J. Biol Chem. 277, 11853-11858. 

Horrocks P, Kilbey BJ. Physical and functional mapping of the transcriptional start sites of Plasmodium falciparum proliferating cell nuclear antigen. Mol Biochem Parasitol. 1996 82 207-15. 

It is apparent from the above discussion that Ki-67 is present in the nucleus of proliferating cells and is an indicator of the growth fraction in tumor cells. It is primarily a DNA-binding protein that plays a crucial role in the maintenance or regulation of cell division. This protein may also function as a matrix for chromosomal DNA or contribute to the condensation of the chromosomes or be involved in breakdown of the nuclear membrane before mitosis (Duchrow et al., 1994). The association of Ki-67 with RNA in the nucleoli and with the DNA with nuclear matrix suggests that the antigen plays a role in transcriptional processes as a structural protein by mediating between nuclear DNA and nucleolar RNA. 

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