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Proliferating cell nuclear antigen (PCNA) has been demonstrated to interact with multiple proteins involved in several metabolic pathways such as DNA replication and repair. However, there have been fewer reports about whether these PCNA-binding proteins influence stability of PCNA. Here, we observed a physical interaction between PCNA and MutT homolog2 (MTH2), a new member of the MutT-related proteins that hydrolyzes 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP). In several unstressed human cancer cell lines and in normal human fibroblast cells, PCNA and MTH2 formed a complex and their mutual binding fragments were confirmed. It was intriguing that PCNA and MTH2 were dissociated dependent on acetylation of PCNA, which in turn induced degradation of PCNA in response to UV irradiation, but not in response to other forms of DNA-damaging stress. To further explore the link between dissociation of PCNA-MTH2 and degradation of PCNA, RNAi against MTH2 was performed to mimic the dissociated status of PCNA to evaluate changes in the half-life of PCNA. Knockdown of MTH2 significantly promoted degradation of PCNA, suggesting that the physiological interaction of PCNA-MTH2 may confer protection from degradation for PCNA, whereas UV irradiation accelerates PCNA degradation by inducing dissociation of PCNA-MTH2. Moreover, secondary to degradation of PCNA, UV-induced inhibition of DNA synthesis or cell cycle progression was enhanced. Collectively, our data demonstrate for the first time that PCNA is protected by this newly identified partner molecule MTH2, which is related to DNA synthesis and cell cycle progression. Proliferating cell nuclear antigen (PCNA) has been demonstrated to interact with multiple proteins involved in several metabolic pathways such as DNA replication and repair. However, there have been fewer reports about whether these PCNA-binding proteins influence stability of PCNA. Here, we observed a physical interaction between PCNA and MutT homolog2 (MTH2), a new member of the MutT-related proteins that hydrolyzes 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP). In several unstressed human cancer cell lines and in normal human fibroblast cells, PCNA and MTH2 formed a complex and their mutual binding fragments were confirmed. It was intriguing that PCNA and MTH2 were dissociated dependent on acetylation of PCNA, which in turn induced degradation of PCNA in response to UV irradiation, but not in response to other forms of DNA-damaging stress. To further explore the link between dissociation of PCNA-MTH2 and degradation of PCNA, RNAi against MTH2 was performed to mimic the dissociated status of PCNA to evaluate changes in the half-life of PCNA. Knockdown of MTH2 significantly promoted degradation of PCNA, suggesting that the physiological interaction of PCNA-MTH2 may confer protection from degradation for PCNA, whereas UV irradiation accelerates PCNA degradation by inducing dissociation of PCNA-MTH2. Moreover, secondary to degradation of PCNA, UV-induced inhibition of DNA synthesis or cell cycle progression was enhanced. Collectively, our data demonstrate for the first time that PCNA is protected by this newly identified partner molecule MTH2, which is related to DNA synthesis and cell cycle progression. Proliferating cell nuclear antigen (PCNA) 3The abbreviations used are: PCNAproliferating cell nuclear antigenMTH2MutT homolog28-oxo-dGTP8-oxo-7,8-dihydrodeoxyguanosine triphosphateGSTglutathione S-transferasePMSFphenylmethylsulfonyl fluorideTSAtrichostatin AROIregion of interestFRETfluorescence resonance energy transferPIPES1,4-piperazinediethanesulfonic acidRNAiRNA interferenceCHXcycloheximideTLStranslesion synthesisRTreverse transcription.3The abbreviations used are: PCNAproliferating cell nuclear antigenMTH2MutT homolog28-oxo-dGTP8-oxo-7,8-dihydrodeoxyguanosine triphosphateGSTglutathione S-transferasePMSFphenylmethylsulfonyl fluorideTSAtrichostatin AROIregion of interestFRETfluorescence resonance energy transferPIPES1,4-piperazinediethanesulfonic acidRNAiRNA interferenceCHXcycloheximideTLStranslesion synthesisRTreverse transcription. is a member of the DNA sliding clamp family and consists of a ring-shaped trimeric complex (1.Indiani C. O'Donnell M. Nat. Rev. Mol. Cell Biol. 2006; 7: 751-761Crossref PubMed Scopus (142) Google Scholar, 2.Moldovan G.L. Pfander B. Jentsch S. Cell. 2007; 129: 665-679Abstract Full Text Full Text PDF PubMed Scopus (1290) Google Scholar, 3.Warbrick E. Bioessays. 2000; 22: 997-1006Crossref PubMed Scopus (353) Google Scholar). Three PCNA monomers, each comprising two similar domains, are joined in a head-to-tail arrangement to form a closed ring (4.Gulbis J.M. Kelman Z. Hurwitz J. O'Donnell M. Kuriyan J. Cell. 1996; 87: 297-306Abstract Full Text Full Text PDF PubMed Scopus (632) Google Scholar, 5.Kong X.P. Onrust R. O'Donnell M. Kuriyan J. Cell. 1992; 69: 425-437Abstract Full Text PDF PubMed Scopus (629) Google Scholar). Because of this unique structure, PCNA encircles the DNA double helix and slides freely along it. PCNA was originally characterized as a DNA polymerase processivity factor and it increases the processivity of DNA synthesis by interacting with polymerase δ (6.Bravo R. Frank R. Blundell P.A. Macdonald-Bravo H. Nature. 1987; 326: 515-517Crossref PubMed Scopus (1636) Google Scholar, 7.Prelich G. Tan C.K. Kostura M. Mathews M.B. So A.G. Downey K.M. Stillman B. Nature. 1987; 326: 517-520Crossref PubMed Scopus (884) Google Scholar). Subsequent studies revealed that PCNA plays an important role in DNA replication (8.Jaskulski D. deRiel J.K. Mercer W.E. Calabretta B. Baserga R. Science. 1988; 240: 1544-1546Crossref PubMed Scopus (359) Google Scholar, 9.Prelich G. Kostura M. Marshak D.R. Mathews M.B. Stillman B. Nature. 1987; 326: 471-475Crossref PubMed Scopus (356) Google Scholar). For example, PCNA not only functions as a protein binding platform to interact with the DNA polymerases, flap endonuclease-1 (Fen1) or DNA ligase I (10.Levin D.S. Bai W. Yao N. O'Donnell M. Tomkinson A.E. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 12863-12868Crossref PubMed Scopus (193) Google Scholar, 11.Hosfield D.J. Mol C.D. Shen B. Tainer J.A. 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Nucleic Acids Res. 2008; 36: 67-75Crossref PubMed Scopus (37) Google Scholar, 17.Dou H. Theriot C.A. Das A. Hegde M.L. Matsumoto Y. Boldogh I. Hazra T.K. Bhakat K.K. Mitra S. J. Biol. Chem. 2008; 283: 3130-3140Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar) and cell cycle control (18.Matsuoka S. Yamaguchi M. Matsukage A. J. Biol. Chem. 1994; 269: 11030-11036Abstract Full Text PDF PubMed Google Scholar, 19.Scorah J. Dong M.Q. Yates 3rd, J.R. Scott M. Gillespie D. McGowan C.H. J. Biol. Chem. 2008; 283: 17250-17259Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 20.Arias E.E. Walter J.C. Nat Cell Biol. 2006; 8: 84-90Crossref PubMed Scopus (256) Google Scholar). proliferating cell nuclear antigen MutT homolog2 8-oxo-7,8-dihydrodeoxyguanosine triphosphate glutathione S-transferase phenylmethylsulfonyl fluoride trichostatin A region of interest fluorescence resonance energy transfer 1,4-piperazinediethanesulfonic acid RNA interference cycloheximide translesion synthesis reverse transcription. proliferating cell nuclear antigen MutT homolog2 8-oxo-7,8-dihydrodeoxyguanosine triphosphate glutathione S-transferase phenylmethylsulfonyl fluoride trichostatin A region of interest fluorescence resonance energy transfer 1,4-piperazinediethanesulfonic acid RNA interference cycloheximide translesion synthesis reverse transcription. Because PCNA is essential for DNA synthesis both in DNA replication and repair, a dynamic balance between PCNA synthesis and degradation is critical for maintaining normal DNA synthesis. Up-regulation of PCNA accelerates DNA synthesis and promotes cell proliferation, such that PCNA is regarded as a general proliferation marker in tumor development. On the other hand, degradation of PCNA leads to inhibition of DNA synthesis (9.Prelich G. Kostura M. Marshak D.R. Mathews M.B. Stillman B. Nature. 1987; 326: 471-475Crossref PubMed Scopus (356) Google Scholar, 21.Engel F.B. Hauck L. Boehm M. Nabel E.G. Dietz R. von Harsdorf R. Mol. Cell. Biol. 2003; 23: 555-565Crossref PubMed Scopus (53) Google Scholar). In this case, in response to inhibition of DNA synthesis by PCNA degradation, both cell proliferation and DNA repair are inhibited, and cells are thus subject to death. In Escherichia coli, MutT protein encoded by the mutT gene has 8-oxo-dGTPase activity, and hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, which is nonutilizable for DNA synthesis, thus preventing misincorporation of 8-oxo-dGTP into DNA (22.Maki H. Sekiguchi M. Nature. 1992; 355: 273-275Crossref PubMed Scopus (781) Google Scholar). 8-Oxo-dGTP is a product of dGTP and into or of DNA a to or to (22.Maki H. Sekiguchi M. Nature. 1992; 355: 273-275Crossref PubMed Scopus (781) Google Scholar, S. M. Nature. PubMed Scopus Google Scholar, H. K. H. Y. T. Sekiguchi M. Nucleic Acids Res. 1997; PubMed Scopus Google Scholar). In a the of of to increases by with that of cells with mutT T. H. Sekiguchi M. Res. PubMed Scopus Google Scholar, M. H. Sekiguchi M. T. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, T. H. Sekiguchi M. 2003; PubMed Scopus Google Scholar). MutT protein is for preventing and maintaining of DNA replication M. T. PubMed Scopus Google Scholar). In addition, is a for MutT in E. and also plays a role in maintaining of DNA replication M. Y. M. H. Sekiguchi M. K. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). MutT is the first MutT-related protein in cells K. M. T. T. S. H. Sekiguchi M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). in cells an of as with that in cells T. A. H. T. Y. Y. H. K. K. F. S. Y. M. T. Sekiguchi M. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus (256) Google Scholar). the in E. cells with that in cells that there other proteins for preventing of of damage induced in the data our and T. Y. H. Sekiguchi M. Res. 2003; PubMed Scopus Google Scholar) have a new member of MutT-related in cells was significantly by of MTH2 T. Y. H. Sekiguchi M. Res. 2003; PubMed Scopus Google Scholar). MTH2 may to cells DNA synthesis. However, from the of the by which MTH2 DNA synthesis has not been functions of both PCNA and MTH2 in DNA synthesis, thus of whether MTH2 with PCNA to DNA replication or repair. In this we that MTH2 with PCNA, and this interaction PCNA However, cells were to UV the interaction of MTH2 and PCNA was and PCNA degradation was DNA synthesis was and cell was cancer cell lines were in with and an of in a fibroblast cells or human cells were in were to UV were the with a UV and was for for to was by as Res. Google Scholar). used were and from were performed as Y. S. L. G. H. Y. J. Y. W. M. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar). cell was with on for was with and a of and to the which were for the were with the were into and protein was by with were in with A for on and the cells were and was the and the was in and the was or protein were by MTH2 or PCNA into the with and or MTH2 was by PCNA or MTH2 into the or with and PCNA was by PCNA into the of was a the or proteins were in E. induced with for and the from of or proteins were with by for and the were with and cell from cells were to the and by were with and and into and the was and by with to PCNA and from was with was and used for in RNA polymerase to the In protein was by and were into cells were observed a and the was performed with were into cells by of the to the for MTH2 or PCNA was into cells by of a for to the To the of protein was for or MTH2 PCNA DNA synthesis was by were a to was for and DNA was with acid DNA was on a and with acid and with or the it was into a for Cell cycle was performed as H. Y. Li L. L. S. Y. W. J. G. Y. J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus Google Scholar). or cells were and with were with cells were on and to the cells were with for were with for and with for cells were with of and with a of for were with fluorescence was with To explore the between PCNA and MTH2, we first whether PCNA with MTH2 the PCNA was with from cell of several human cell cancer cell lines and human fibroblast cells and human cells It was of interest to that PCNA and MTH2 formed a complex in to whether the interaction was a a was in PCNA in was with a protein and was performed with in PCNA formed a complex with protein in To further of PCNA and MTH2 were into fragments to in that the acid region of MTH2 and acid region of PCNA are the fragments involved in the interaction of PCNA and the of MTH2 was from MTH2 it human MTH2 with protein in or by RNAi in that PCNA with MTH2 in To the of DNA-damaging on the PCNA-MTH2 cells were with or a DNA that DNA H. Y. Li L. L. S. Y. W. J. G. Y. J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Y. S. W. Z. T. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and were It was a to that PCNA with was in cells and this was dependent on UV or UV time For example, with cells, the interaction of these proteins was a of and a of in cells as by In addition, UV irradiation the interaction of these proteins was and It is that there were changes in the interaction of these proteins in cells with or which that UV may have a unique to a in the interaction of PCNA-MTH2. To whether the in interaction between PCNA and MTH2 is to dissociation of these proteins or of protein and were performed to evaluate of PCNA and MTH2 that of both proteins and were a of UV irradiation and that UV irradiation to and not to a in the of In addition, the was performed to the of dissociation of PCNA and MTH2 in response to UV cells were with and In this the was used to the of the and of the both and region of on the of A and the fluorescence of and In unstressed cells, of both and of the the fluorescence of the in the was that between PCNA and However, in cells, both and of the were the fluorescence of the in the suggesting that was between these two the energy transfer was in cells as with that in cells data demonstrate that the interaction between PCNA and MTH2 was in response to UV acetylation and have been to related to the PCNA H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. W. Li R. Nat. Cell Biol. 2006; 8: PubMed Scopus Google Scholar), which a as to whether of PCNA is involved in UV-induced To evaluate this cell from cells was first with or and was with in we not an in PCNA or However, UV to acetylation of PCNA and the acetylation was for to UV irradiation In addition, to the of these cells and cells were with and were to of or of in cells H. Y. Li L. L. S. Y. W. J. G. Y. J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus Google Scholar). factor was to the of B. M. H. Proc. Natl. Acad. Sci. U.S.A. 87: PubMed Scopus Google Scholar). was to the acetylation of Y. S. L. G. H. Y. J. Y. W. M. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar). in these significantly induced of these which were that acetylation is a unique of PCNA in response to UV To whether of PCNA by acetylation is related to dissociation of these cells were with a to mimic protein acetylation and a was that also induced acetylation of PCNA and dissociation of these proteins However, the of the two proteins was in cells In addition, to which acetylation is critical for the interaction of these two several of PCNA were PCNA to MTH2 and of PCNA or was and in However, it was that UV irradiation not an in acetylation as with that of PCNA UV not to the dissociation of and MTH2 that acetylation of PCNA may a role in interaction of MTH2 and PCNA. PCNA is a protein and half-life is For example, in cells, the half-life of PCNA is R. Macdonald-Bravo H. J. Cell Biol. 1987; PubMed Scopus Google Scholar). cycloheximide an of protein synthesis, was into the for to the of PCNA in cells However, in response to UV irradiation, the half-life of PCNA was a time For example, the of PCNA not in the time UV However, the PCNA was to and further to as with the of PCNA UV irradiation Because the PCNA was not in response to UV irradiation it is that UV irradiation accelerates degradation of PCNA. To whether there is a link between UV-induced dissociation of these proteins and UV-induced degradation of PCNA, the half-life of PCNA in or cells was also A similar was in the cells, in which the half-life of PCNA was to and of MTH2 was used to the dissociated status of PCNA and of MTH2 RNAi is in of PCNA was for to with in RNAi cells and However, the half-life of PCNA in cells was to a of between and and the of PCNA was in cells as with that in RNAi cells data that PCNA dissociated from complex with MTH2 has a half-life and is To further the of PCNA degradation, or cells were in the of the of PCNA induced by UV irradiation or was in cells in the of A and Moreover, in UV or MTH2 cells was with that in cells demonstrate that the degradation of PCNA a It is that PCNA is involved in metabolic pathways and is in involved in DNA synthesis. to the that DNA synthesis may by MTH2 in response to UV an was used to evaluate DNA synthesis and cell in a in was in cells, and this was by of PCNA. To further whether of MTH2 DNA synthesis by PCNA degradation, was into the for that from was in cells, and this was also by of PCNA data that of MTH2 was with inhibition of DNA synthesis the degradation of PCNA. In to DNA synthesis, PCNA is also for progression by interacting with the complex H. Y. D. Mol. Biol. Cell. PubMed Scopus Google Scholar). further changes in the cell cycle in or an was observed in both cells and cells with the For example, the of UV or RNAi against MTH2, the cells in to from and to from that UV irradiation induced changes in the cell cycle may related to PCNA of interest in this is the of MTH2 dissociation from PCNA in response to UV To explore the of PCNA on MTH2 activity, cells were with to the dissociation of PCNA and MTH2, and the was with MTH2, as a 8-oxo-dGTP to 8-oxo-dGMP, and the misincorporation of into there was a between the of MTH2 and the of a cells a in as a a an in of was in cells, with control However, the between two was not by a It that PCNA may not a factor to the of data that the newly identified molecule MTH2 is of in functions in with PCNA. In our demonstrate that the interaction between PCNA and MTH2 may PCNA from these proteins were dissociated in response to UV irradiation, degradation of PCNA was and DNA synthesis UV irradiation has been to in cell For example, human cell and human cell were to UV-induced R. M. J. 1997; Full Text PDF PubMed Scopus Google Scholar, A. R. Y. K. H. D. T.A. T. J. Full Text PDF PubMed Scopus Google Scholar, J. Biol. PubMed Scopus Google Scholar). In this to induced by UV irradiation, we used cells to the as cells were to UV R. D. L. G. A. J. Cell. 2008; PubMed Scopus Google Scholar, M. W. Res. 2000; Google Scholar). In addition, a tumor is in cell cancer H. M.R. C. K. C. T. D. L. Li D. L. J. J. X. P.A. M. D.J. N. K.K. Nature. 2007; PubMed Scopus Google Scholar). in to cell cancer cell lines and we also human cell and human cell to further evaluate the interaction of PCNA-binding such as polymerase and a to as a A. E. R. J.K. J. Biol. Chem. 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In this we observed that acetylation of PCNA was induced by UV irradiation, and the dissociation of PCNA and MTH2 and that acetylation of PCNA is a critical which may about a in PCNA and in turn the interaction of MTH2 and PCNA. PCNA functions have been the by which functions are to In this we observed that the half-life of PCNA was in and cells and observed that the of PCNA was by the A and However, PCNA not in cells as with cells, which is with that has been by other Y. W. Li R. Nat. Cell Biol. 2006; 8: PubMed Scopus Google Scholar, M. F. F. J. Biol. Chem. 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