{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:50:18Z","timestamp":1760147418652,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["140\/18","458","#238","188\/4-1"],"award-info":[{"award-number":["140\/18","458","#238","188\/4-1"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Israel Cancer Research Fund","award":["140\/18","458","#238","188\/4-1"],"award-info":[{"award-number":["140\/18","458","#238","188\/4-1"]}]},{"name":"Minerva Stiftung","award":["140\/18","458","#238","188\/4-1"],"award-info":[{"award-number":["140\/18","458","#238","188\/4-1"]}]},{"DOI":"10.13039\/501100001659","name":"DFG-Middle East","doi-asserted-by":"publisher","award":["140\/18","458","#238","188\/4-1"],"award-info":[{"award-number":["140\/18","458","#238","188\/4-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Several DNA polymerases participate in DNA synthesis during genome replication and DNA repair. PCNA, a homotrimeric ring, acts as a processivity factor for DNA polymerases. PCNA also acts as a \u201clanding pad\u201d for proteins that interact with chromatin and DNA at the moving fork. The interaction between PCNA and polymerase delta (Pol\u03b4) is mediated by PIPs (PCNA-interacting peptides), in particular the one on Pol32, a regulatory subunit of Pol\u03b4. Here, we demonstrate that pol3-01, an exonuclease mutant of Pol\u03b4\u2019s catalytic subunit, exhibits a weak interaction with Pol30 compared to the WT DNA polymerase. The weak interaction activates DNA bypass pathways, leading to increased mutagenesis and sister chromatid recombination. Strengthening pol3-01\u2032s weak interaction with PCNA suppresses most of the phenotypes. Our results are consistent with a model in which Pol3-01 tends to detach from the chromatin, allowing an easier replacement of Pol\u03b4 by the trans-lesion synthesis polymerase Zeta (Polz), thus leading to the increased mutagenic phenotype.<\/jats:p>","DOI":"10.3390\/genes14020391","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T02:35:10Z","timestamp":1675391710000},"page":"391","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Role for the Interactions between Pol\u03b4 and PCNA Revealed by Analysis of pol3-01 Yeast Mutants"],"prefix":"10.3390","volume":"14","author":[{"given":"Shaked","family":"Nir Heyman","sequence":"first","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Golan","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Batia","family":"Liefshitz","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7934-3342","authenticated-orcid":false,"given":"Martin","family":"Kupiec","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.cub.2005.12.002","article-title":"Evidence that errors made by DNA polymerase \u03b1 are corrected by DNA polymerase \u03b4","volume":"16","author":"Pavlov","year":"2006","journal-title":"Curr. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1146\/annurev-biochem-061516-044709","article-title":"Eukaryotic DNA Replication Fork","volume":"86","author":"Burgers","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1126\/science.1144067","article-title":"Yeast DNA polymerase epsilon participates in leading-strand DNA replication","volume":"317","author":"Pursell","year":"2007","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.molcel.2008.02.022","article-title":"Division of labor at the eukaryotic replication fork","volume":"30","author":"Gordenin","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7506","DOI":"10.1073\/pnas.85.20.7506","article-title":"The yeast analog of mammalian cyclin\/proliferating-cell nuclear antigen interacts with mammalian DNA polymerase delta","volume":"85","author":"Bauer","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1093\/emboj\/17.8.2412","article-title":"Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen","volume":"17","author":"Jonsson","year":"1998","journal-title":"EMBO J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1002\/1521-1878(200011)22:11<997::AID-BIES6>3.0.CO;2-#","article-title":"The puzzle of PCNA\u2019s many partners","volume":"22","author":"Warbrick","year":"2000","journal-title":"BioEssays"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1002\/j.1460-2075.1989.tb03580.x","article-title":"Structure and function of the Saccharomyces cerevisiae CDC2 gene encoding the large subunit of DNA polymerase III","volume":"8","author":"Boulet","year":"1989","journal-title":"EMBO J"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"19747","DOI":"10.1074\/jbc.273.31.19747","article-title":"Characterization of the two small subunits of Saccharomyces cerevisiae DNA polymerase \u03b4","volume":"273","author":"Gerik","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"43824","DOI":"10.1074\/jbc.M108842200","article-title":"Structure of DNA polymerase \u03b4 from Saccharomyces cerevisiae","volume":"276","author":"Johansson","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1002\/(SICI)1097-0061(19970930)13:12<1181::AID-YEA169>3.0.CO;2-O","article-title":"Disruption of six novel yeast genes reveals three genes essential for vegetative growth and one required for growth at low temperature","volume":"13","author":"Huang","year":"1997","journal-title":"Yeast"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1074\/jbc.M310362200","article-title":"The Pol32 subunit of DNA polymerase \u03b4 contains separable domains for processive replication and proliferating cell nuclear antigen (PCNA) binding","volume":"279","author":"Johansson","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/s41594-019-0305-z","article-title":"Cryo-EM structure and dynamics of eukaryotic DNA polymerase \u03b4 holoenzyme","volume":"26","author":"Jain","year":"2019","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17927","DOI":"10.1073\/pnas.1109981108","article-title":"PCNA binding domains in all three subunits of yeast DNA polymerase \u03b4 modulate its function in DNA replication","volume":"108","author":"Acharya","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1038\/emboj.2013.9","article-title":"Srs2 mediates PCNA-SUMO-dependent inhibition of DNA repair synthesis","volume":"32","author":"Burkovics","year":"2013","journal-title":"EMBO J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1007\/s00294-020-01082-y","article-title":"How yeast cells deal with stalled replication forks","volume":"66","author":"Arbel","year":"2020","journal-title":"Curr. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"fuaa038","DOI":"10.1093\/femsre\/fuaa038","article-title":"DNA damage bypass pathways and their effect on mutagenesis in yeast","volume":"45","author":"Arbel","year":"2021","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23360","DOI":"10.1074\/jbc.272.37.23360","article-title":"Yeast DNA repair proteins Rad6 and Rad18 form a heterodimer that has ubiquitin conjugating, DNA binding, and ATP hydrolytic activities","volume":"272","author":"Bailly","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nature00991","article-title":"RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO","volume":"419","author":"Hoege","year":"2002","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1126\/science.272.5268.1646","article-title":"Thymine-thymine dimer bypass by yeast DNA polymerase \u03b6","volume":"272","author":"Nelson","year":"1996","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/genetics\/96.4.841","article-title":"The effects of three PSO genes on induced mutagenesis: A novel class of mutationally defective yeast","volume":"96","author":"Cassier","year":"1980","journal-title":"Genetics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1093\/genetics\/96.4.819","article-title":"The origin of spontaneous mutation in Saccharomyces cerevisiae","volume":"96","author":"Quah","year":"1980","journal-title":"Genetics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/cr.2007.117","article-title":"DNA polymerase zeta (pol \u03b6) in higher eukaryotes","volume":"18","author":"Gan","year":"2008","journal-title":"Cell Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1146\/annurev.biochem.71.083101.124707","article-title":"Error-prone repair DNA polymerases in prokaryotes and eukaryotes","volume":"71","author":"Goodman","year":"2002","journal-title":"Annu. Rev. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.dnarep.2016.05.008","article-title":"DNA damage tolerance by recombination: Molecular pathways and DNA structures","volume":"44","author":"Branzei","year":"2016","journal-title":"DNA Repair"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15954","DOI":"10.1073\/pnas.0504586102","article-title":"The error-free component of the RAD6\/RAD18 DNA damage tolerance pathway of budding yeast employs sister-strand recombination","volume":"102","author":"Zhang","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3388","DOI":"10.1093\/emboj\/19.13.3388","article-title":"Two RING finger proteins mediate cooperation between ubiquitin-conjugating enzymes in DNA repair","volume":"19","author":"Ulrich","year":"2000","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1128\/MCB.22.7.2419-2426.2002","article-title":"Requirement of RAD5 and MMS2 for postreplication repair of UV-damaged DNA in Saccharomyces cerevisiae","volume":"22","author":"Prakash","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1093\/hmg\/ddt131","article-title":"DNA polymerase \u03b5 and \u03b4 exonuclease domain mutations in endometrial cancer","volume":"22","author":"Church","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/ng.2503","article-title":"Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas","volume":"45","author":"Palles","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1002\/j.1460-2075.1993.tb05790.x","article-title":"Pathway correcting DNA replication errors in Saccharomyces cerevisiae","volume":"12","author":"Morrison","year":"1993","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1093\/genetics\/132.2.387","article-title":"Sister chromatids are preferred over homologs as substrates for recombinational repair in Saccharomyces cerevisiae","volume":"132","author":"Kadyk","year":"1992","journal-title":"Genetics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1007\/BF02986080","article-title":"The distribution of the numbers of mutants in bacterial populations","volume":"49","author":"Lea","year":"1949","journal-title":"J. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1002\/j.1460-2075.1991.tb07751.x","article-title":"The 3\u2032 to 5\u2032 exonuclease activity located in the DNA polymerase delta subunit of Saccharomyces cerevisiae is required for accurate replication","volume":"10","author":"Simon","year":"1991","journal-title":"EMBO J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5122","DOI":"10.1073\/pnas.091095198","article-title":"The 3\u2032-->5\u2032 exonuclease of DNA polymerase \u03b4 can substitute for the 5\u2032 flap endonuclease Rad27\/Fen1 in processing Okazaki fragments and preventing genome instability","volume":"98","author":"Jin","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1128\/MCB.19.3.2000","article-title":"The 3\u2032-->5\u2032 exonucleases of DNA polymerases delta and epsilon and the 5'-->3' exonuclease Exo1 have major roles in postreplication mutation avoidance in Saccharomyces cerevisiae","volume":"19","author":"Tran","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1534\/genetics.107.071506","article-title":"Estimating the per-base-pair mutation rate in the yeast Saccharomyces cerevisiae","volume":"178","author":"Lang","year":"2008","journal-title":"Genetics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2859","DOI":"10.1128\/MCB.17.5.2859","article-title":"Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants","volume":"17","author":"Tran","year":"1997","journal-title":"Mol. Cell. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12455","DOI":"10.1073\/pnas.1206052109","article-title":"Pol31 and Pol32 subunits of yeast DNA polymerase delta are also essential subunits of DNA polymerase zeta","volume":"109","author":"Johnson","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1093\/genetics\/146.4.1239","article-title":"Involvement of the yeast DNA polymerase delta in DNA repair in vivo","volume":"146","author":"Giot","year":"1997","journal-title":"Genetics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1007\/BF00294684","article-title":"Suppressors of thermosensitive mutations in the DNA polymerase delta gene of Saccharomyces cerevisiae","volume":"246","author":"Giot","year":"1995","journal-title":"Mol. Gen. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1038\/s41467-020-15912-7","article-title":"Mutational signatures are jointly shaped by DNA damage and repair","volume":"11","author":"Volkova","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0021-9258(19)45781-5","article-title":"Enzymatic synthesis of deoxyribonucleic acid. 36. A proofreading function for the 3\u2032 leads to 5\u2032 exonuclease activity in deoxyribonucleic acid polymerases","volume":"247","author":"Brutlag","year":"1972","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/S0092-8674(88)90189-4","article-title":"Exonucleolytic proofreading","volume":"53","author":"Kunkel","year":"1988","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1128\/MCB.25.1.461-471.2005","article-title":"The multiple biological roles of the 3\u2032-->5\u2032 exonuclease of Saccharomyces cerevisiae DNA polymerase delta require switching between the polymerase and exonuclease domains","volume":"25","author":"Jin","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/BF00280418","article-title":"The 3\u2032-->5\u2032 exonucleases of both DNA polymerases delta and epsilon participate in correcting errors of DNA replication in Saccharomyces cerevisiae","volume":"242","author":"Morrison","year":"1994","journal-title":"Mol. Gen. Genet."},{"doi-asserted-by":"crossref","unstructured":"Hendel, A., Krijger, P.H., Diamant, N., Goren, Z., Langerak, P., Kim, J., Reissner, T., Lee, K.Y., Geacintov, N.E., and Carell, T. (2011). PCNA ubiquitination is important, but not essential for translesion DNA synthesis in mammalian cells. PLoS Genet., 7.","key":"ref_47","DOI":"10.1371\/journal.pgen.1002262"},{"doi-asserted-by":"crossref","unstructured":"Tellier-Lebegue, C., Dizet, E., Ma, E., Veaute, X., Coic, E., Charbonnier, J.B., and Maloisel, L. (2017). The translesion DNA polymerases Pol \u03b6 and Rev1 are activated independently of PCNA ubiquitination upon UV radiation in mutants of DNA polymerase \u03b4. PLoS Genet., 13.","key":"ref_48","DOI":"10.1371\/journal.pgen.1007119"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.molcel.2015.10.041","article-title":"Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements","volume":"60","author":"Sakofsky","year":"2015","journal-title":"Mol. Cell"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/391\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:22:23Z","timestamp":1760120543000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/391"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,2]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["genes14020391"],"URL":"https:\/\/doi.org\/10.3390\/genes14020391","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2023,2,2]]}}}