scholarly journals p53-Mediated Regulation of Proliferating Cell Nuclear Antigen Expression in Cells Exposed to Ionizing Radiation

1999 ◽  
Vol 19 (1) ◽  
pp. 12-20 ◽  
Author(s):  
Jin Xu ◽  
Gilbert F. Morris
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Ionizing Radiation ◽  
Proliferating Cell Nuclear Antigen ◽  
Cellular Response ◽  
Nuclear Antigen ◽  
Dominant Negative Mutant ◽  
Mrna Levels ◽  
Mobility Shift ◽  
Proliferating Cell

ABSTRACT The proliferating cell nuclear antigen (PCNA) is a highly conserved cellular protein that functions both in DNA replication and in DNA repair. Exposure of a rat embryo fibroblast cell line (CREF cells) to γ radiation induced simultaneous expression of PCNA with the p53 tumor suppressor protein and the cyclin-dependent kinase inhibitor p21WAF1/Cip1. PCNA mRNA levels transiently increased in serum-starved cells exposed to ionizing radiation, an observation suggesting that the radiation-associated increase in PCNA expression could be dissociated from cell cycle progression. Irradiation of CREF cells activated a transiently expressed PCNA promoter chloramphenicol acetyltransferase construct through p53 binding sequences via a mechanism blocked by a dominant negative mutant p53. Electrophoretic mobility shift assays with nuclear extracts prepared from irradiated CREF cells produced four p53-specific DNA-protein complexes with the PCNA p53 binding site. Addition of monoclonal antibody PAb421 (p53-specific) or AC238 (specific to the transcriptional coactivator p300/CREB binding protein) to the mobility shift assay distinguished different forms of p53 that changed in relative abundance with time after irradiation. These findings suggest a complex cellular response to DNA damage in which p53 transiently activates expression of PCNA for the purpose of limited DNA repair. In a population of nongrowing cells with diminished PCNA levels, this pathway may be crucial to survival following DNA damage.

scholarly journals Postreplication Repair and PCNA Modification in Schizosaccharomyces pombe

2006 ◽  
Vol 17 (7) ◽  
pp. 2976-2985 ◽  
Author(s):  
Jonathan Frampton ◽  
Anja Irmisch ◽  
Catherine M. Green ◽  
Andrea Neiss ◽  
Michelle Trickey ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Schizosaccharomyces Pombe ◽  
Uv Irradiation ◽  
Proliferating Cell Nuclear Antigen ◽  
S Phase ◽  
Cell Cycle Checkpoints ◽  
Nuclear Antigen ◽  
Proliferating Cell

Ubiquitination of proliferating cell nuclear antigen (PCNA) plays a crucial role in regulating replication past DNA damage in eukaryotes, but the detailed mechanisms appear to vary in different organisms. We have examined the modification of PCNA in Schizosaccharomyces pombe. We find that, in response to UV irradiation, PCNA is mono- and poly-ubiquitinated in a manner similar to that in Saccharomyces cerevisiae. However in undamaged Schizosaccharomyces pombe cells, PCNA is ubiquitinated in S phase, whereas in S. cerevisiae it is sumoylated. Furthermore we find that, unlike in S. cerevisiae, mutants defective in ubiquitination of PCNA are also sensitive to ionizing radiation, and PCNA is ubiquitinated after exposure of cells to ionizing radiation, in a manner similar to the response to UV-irradiation. We show that PCNA modification and cell cycle checkpoints represent two independent signals in response to DNA damage. Finally, we unexpectedly find that PCNA is ubiquitinated in response to DNA damage when cells are arrested in G2.

scholarly journals ATM Protein Physically and Functionally Interacts with Proliferating Cell Nuclear Antigen to Regulate DNA Synthesis

2012 ◽  
Vol 287 (15) ◽  
pp. 12445-12454 ◽  
Author(s):  
Armin M. Gamper ◽  
Serah Choi ◽  
Yoshihiro Matsumoto ◽  
Dibyendu Banerjee ◽  
Alan E. Tomkinson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Ionizing Radiation ◽  
Dna Synthesis ◽  
Dna Polymerase ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Atm Kinase ◽  
Atm Protein ◽  
Proliferating Cell

Ataxia telangiectasia (A-T) is a pleiotropic disease, with a characteristic hypersensitivity to ionizing radiation that is caused by biallelic mutations in A-T mutated (ATM), a gene encoding a protein kinase critical for the induction of cellular responses to DNA damage, particularly to DNA double strand breaks. A long known characteristic of A-T cells is their ability to synthesize DNA even in the presence of ionizing radiation-induced DNA damage, a phenomenon termed radioresistant DNA synthesis. We previously reported that ATM kinase inhibition, but not ATM protein disruption, blocks sister chromatid exchange following DNA damage. We now show that ATM kinase inhibition, but not ATM protein disruption, also inhibits DNA synthesis. Investigating a potential physical interaction of ATM with the DNA replication machinery, we found that ATM co-precipitates with proliferating cell nuclear antigen (PCNA) from cellular extracts. Using bacterially purified ATM truncation mutants and in vitro translated PCNA, we showed that the interaction is direct and mediated by the C terminus of ATM. Indeed, a 20-amino acid region close to the kinase domain is sufficient for strong binding to PCNA. This binding is specific to ATM, because the homologous regions of other PIKK members, including the closely related kinase A-T and Rad3-related (ATR), did not bind PCNA. ATM was found to bind two regions in PCNA. To examine the functional significance of the interaction between ATM and PCNA, we tested the ability of ATM to stimulate DNA synthesis by DNA polymerase δ, which is implicated in both DNA replication and DNA repair processes. ATM was observed to stimulate DNA polymerase activity in a PCNA-dependent manner.

scholarly journals Oxidative DNA Damage Bypass in Arabidopsis thaliana Requires DNA Polymerase λ and Proliferating Cell Nuclear Antigen 2

2011 ◽  
Vol 23 (2) ◽  
pp. 806-822 ◽  
Author(s):  
Alessandra Amoroso ◽  
Lorenzo Concia ◽  
Caterina Maggio ◽  
Cécile Raynaud ◽  
Catherine Bergounioux ◽  
...  
Keyword(s):  
Dna Damage ◽  
Arabidopsis Thaliana ◽  
Dna Polymerase ◽  
Proliferating Cell Nuclear Antigen ◽  
Oxidative Dna Damage ◽  
Nuclear Antigen ◽  
Dna Polymerase Λ ◽  
Proliferating Cell

Proliferating cell nuclear antigen destabilizes c-Abl tyrosine kinase and regulates cell apoptosis in response to DNA damage

APOPTOSIS ◽  
2009 ◽  
Vol 14 (3) ◽  
pp. 268-275 ◽  
Author(s):  
Xiang He ◽  
Congwen Wei ◽  
Ting Song ◽  
Jing Yuan ◽  
Yanhong Zhang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tyrosine Kinase ◽  
Cell Apoptosis ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Abl Tyrosine Kinase ◽  
Proliferating Cell

scholarly journals Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitination

2006 ◽  
Vol 175 (5) ◽  
pp. 703-708 ◽  
Author(s):  
Akira Motegi ◽  
Raman Sood ◽  
Helen Moinova ◽  
Sanford D. Markowitz ◽  
Pu Paul Liu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Proliferating Cell Nuclear Antigen ◽  
Genotoxic Stress ◽  
Suppressor Gene ◽  
Nuclear Antigen ◽  
Putative Tumor Suppressor Gene ◽  
Ubiquitin Ligase E3 ◽  
Proliferating Cell ◽  
Dependent Pathway

Differential modifications of proliferating cell nuclear antigen (PCNA) determine DNA repair pathways at stalled replication forks. In yeast, PCNA monoubiquitination by the ubiquitin ligase (E3) yRad18 promotes translesion synthesis (TLS), whereas the lysine-63–linked polyubiquitination of PCNA by yRad5 (E3) promotes the error-free mode of bypass. The yRad5-dependent pathway is important to prevent genomic instability during replication, although its exact molecular mechanism is poorly understood. This mechanism has remained totally elusive in mammals because of the lack of apparent RAD5 homologues. We report that a putative tumor suppressor gene, SHPRH, is a human orthologue of yeast RAD5. SHPRH associates with PCNA, RAD18, and the ubiquitin-conjugating enzyme UBC13 (E2) and promotes methyl methanesulfonate (MMS)–induced PCNA polyubiquitination. The reduction of SHPRH by stable short hairpin RNA increases sensitivity to MMS and enhances genomic instability. Therefore, the yRad5/SHPRH-dependent pathway is a conserved and fundamental DNA repair mechanism that protects the genome from genotoxic stress.

Interaction between proliferating cell nuclear antigen (PCNA) and a DnaJ induced by DNA damage

2005 ◽  
Vol 118 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Taichi Yamamoto ◽  
Yoko Mori ◽  
Toyotaka Ishibashi ◽  
Yukinobu Uchiyama ◽  
Tadamasa Ueda ◽  
...  
Keyword(s):  
Dna Damage ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Proliferating Cell
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