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.

In human hepatocellular carcinoma in cirrhosis proliferating cell nuclear antigen (PCNA) is involved in cell proliferation and cooperates with P21 in DNA repair

2003 ◽  
Vol 39 (6) ◽  
pp. 997-1003 ◽  
Author(s):  
Laura Gramantieri ◽  
Davide Trerè ◽  
Pasquale Chieco ◽  
Michela Lacchini ◽  
Catia Giovannini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Dna Repair ◽  
Proliferating Cell Nuclear Antigen ◽  
Human Hepatocellular Carcinoma ◽  
Nuclear Antigen ◽  
Proliferating Cell

scholarly journals Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks

2008 ◽  
Vol 105 (34) ◽  
pp. 12411-12416 ◽  
Author(s):  
A. Motegi ◽  
H.-J. Liaw ◽  
K.-Y. Lee ◽  
H. P. Roest ◽  
A. Maas ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Replication Forks ◽  
Stalled Replication Forks ◽  
Proliferating Cell

Proliferating cell nuclear antigen-dependent abasic site repair in Xenopus laevis oocytes: an alternative pathway of base excision DNA repair

1994 ◽  
Vol 14 (9) ◽  
pp. 6187-6197
Author(s):  
Y Matsumoto ◽  
K Kim ◽  
D F Bogenhagen
Keyword(s):  
Dna Polymerase ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Dna Polymerase Delta ◽  
Polymerase Beta ◽  
Ap Sites ◽  
Base Excision ◽  
Proliferating Cell ◽  
Dependent Pathway ◽  
Ap Site

DNA damage frequently leads to the production of apurinic/apyrimidinic (AP) sites, which are presumed to be repaired through the base excision pathway. For detailed analyses of this repair mechanism, a synthetic analog of an AP site, 3-hydroxy-2-hydroxymethyltetrahydrofuran (tetrahydrofuran), has been employed in a model system. Tetrahydrofuran residues are efficiently repaired in a Xenopus laevis oocyte extract in which most repair events involve ATP-dependent incorporation of no more than four nucleotides (Y. Matsumoto and D. F. Bogenhagen, Mol. Cell. Biol. 9:3750-3757, 1989; Y. Matsumoto and D. F. Bogenhagen, Mol. Cell. Biol. 11:4441-4447, 1991). Using a series of column chromatography procedures to fractionate X. laevis ovarian extracts, we developed a reconstituted system of tetrahydrofuran repair with five fractions, three of which were purified to near homogeneity: proliferating cell nuclear antigen (PCNA), AP endonuclease, and DNA polymerase delta. This PCNA-dependent system repaired natural AP sites as well as tetrahydrofuran residues. DNA polymerase beta was able to replace DNA polymerase delta only for repair of natural AP sites in a reaction that did not require PCNA. DNA polymerase alpha did not support repair of either type of AP site. This result indicates that AP sites can be repaired by two distinct pathways, the PCNA-dependent pathway and the DNA polymerase beta-dependent pathway.

scholarly journals Proliferating cell nuclear antigen-dependent abasic site repair in Xenopus laevis oocytes: an alternative pathway of base excision DNA repair.

1994 ◽  
Vol 14 (9) ◽  
pp. 6187-6197 ◽  
Author(s):  
Y Matsumoto ◽  
K Kim ◽  
D F Bogenhagen
Keyword(s):  
Dna Polymerase ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Dna Polymerase Delta ◽  
Polymerase Beta ◽  
Ap Sites ◽  
Base Excision ◽  
Proliferating Cell ◽  
Dependent Pathway ◽  
Ap Site

DNA damage frequently leads to the production of apurinic/apyrimidinic (AP) sites, which are presumed to be repaired through the base excision pathway. For detailed analyses of this repair mechanism, a synthetic analog of an AP site, 3-hydroxy-2-hydroxymethyltetrahydrofuran (tetrahydrofuran), has been employed in a model system. Tetrahydrofuran residues are efficiently repaired in a Xenopus laevis oocyte extract in which most repair events involve ATP-dependent incorporation of no more than four nucleotides (Y. Matsumoto and D. F. Bogenhagen, Mol. Cell. Biol. 9:3750-3757, 1989; Y. Matsumoto and D. F. Bogenhagen, Mol. Cell. Biol. 11:4441-4447, 1991). Using a series of column chromatography procedures to fractionate X. laevis ovarian extracts, we developed a reconstituted system of tetrahydrofuran repair with five fractions, three of which were purified to near homogeneity: proliferating cell nuclear antigen (PCNA), AP endonuclease, and DNA polymerase delta. This PCNA-dependent system repaired natural AP sites as well as tetrahydrofuran residues. DNA polymerase beta was able to replace DNA polymerase delta only for repair of natural AP sites in a reaction that did not require PCNA. DNA polymerase alpha did not support repair of either type of AP site. This result indicates that AP sites can be repaired by two distinct pathways, the PCNA-dependent pathway and the DNA polymerase beta-dependent pathway.

scholarly journals Dependence of nucleotide substitutions on Ung2, Msh2, and PCNA-Ub during somatic hypermutation

2009 ◽  
Vol 206 (12) ◽  
pp. 2603-2611 ◽  
Author(s):  
Peter H.L. Krijger ◽  
Petra Langerak ◽  
Paul C.M. van den Berk ◽  
Heinz Jacobs
Keyword(s):  
B Cells ◽  
Proliferating Cell Nuclear Antigen ◽  
Mutation Frequency ◽  
Somatic Hypermutation ◽  
Nuclear Antigen ◽  
Immunoglobulin Genes ◽  
Nucleotide Substitutions ◽  
High Affinity ◽  
Proliferating Cell ◽  
Dependent Pathway

During somatic hypermutation (SHM), B cells introduce mutations into their immunoglobulin genes to generate high affinity antibodies. Current models suggest a separation in the generation of G/C transversions by the Ung2-dependent pathway and the generation of A/T mutations by the Msh2/ubiquitinated proliferating cell nuclear antigen (PCNA-Ub)–dependent pathway. It is currently unknown whether these pathways compete to initiate mutagenesis and whether PCNA-Ub functions downstream of Ung2. Furthermore, these models do not explain why mice lacking Msh2 have a more than twofold reduction in the total mutation frequency. Our data indicate that PCNA-Ub is required for A/T mutagenesis downstream of both Msh2 and Ung2. Furthermore, we provide evidence that both pathways are noncompetitive to initiate mutagenesis and even collaborate to generate half of all G/C transversions. These findings significantly add to our understanding of SHM and necessitate an update of present SHM models.

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