Dissecting PCNA function with a systematically designed mutant library in yeast
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摘要
Proliferating cell nuclear antigen(PCNA), encoded by POL30 in Saccharomyces cerevisiae, is a key component of DNA metabolism. Here, a library consisting of 304 PCNA mutants was designed and constructed to probe the contribution of each residue to the biological function of PCNA. Five regions with elevated sensitivity to DNA damaging reagents were identified using high-throughput phenotype screening. Using a series of genetic and biochemical analyses, we demonstrated that one particular mutant, K168 A, has defects in the DNA damage tolerance(DDT) pathway by disrupting the interaction between PCNA and Rad5. Subsequent domain analysis showed that the PCNA-Rad5 interaction is a prerequisite for the function of Rad5 in DDT. Our study not only provides a resource in the form of a library of versatile mutants to study the functions of PCNA, but also reveals a key residue on PCNA(K168)which highlights the importance of the PCNA-Rad5 interaction in the template switching(TS) pathway.
Proliferating cell nuclear antigen(PCNA), encoded by POL30 in Saccharomyces cerevisiae, is a key component of DNA metabolism. Here, a library consisting of 304 PCNA mutants was designed and constructed to probe the contribution of each residue to the biological function of PCNA. Five regions with elevated sensitivity to DNA damaging reagents were identified using high-throughput phenotype screening. Using a series of genetic and biochemical analyses, we demonstrated that one particular mutant, K168 A, has defects in the DNA damage tolerance(DDT) pathway by disrupting the interaction between PCNA and Rad5. Subsequent domain analysis showed that the PCNA-Rad5 interaction is a prerequisite for the function of Rad5 in DDT. Our study not only provides a resource in the form of a library of versatile mutants to study the functions of PCNA, but also reveals a key residue on PCNA(K168)which highlights the importance of the PCNA-Rad5 interaction in the template switching(TS) pathway.
Proliferating cell nuclear antigen(PCNA), encoded by POL30 in Saccharomyces cerevisiae, is a key component of DNA metabolism. Here, a library consisting of 304 PCNA mutants was designed and constructed to probe the contribution of each residue to the biological function of PCNA. Five regions with elevated sensitivity to DNA damaging reagents were identified using high-throughput phenotype screening. Using a series of genetic and biochemical analyses, we demonstrated that one particular mutant, K168 A, has defects in the DNA damage tolerance(DDT) pathway by disrupting the interaction between PCNA and Rad5. Subsequent domain analysis showed that the PCNA-Rad5 interaction is a prerequisite for the function of Rad5 in DDT. Our study not only provides a resource in the form of a library of versatile mutants to study the functions of PCNA, but also reveals a key residue on PCNA(K168)which highlights the importance of the PCNA-Rad5 interaction in the template switching(TS) pathway.
引文
Ahne,F.,Jha,B.,Eckardt-Schupp,F.,1997.The RAD5 gene product is involved in the avoidance of non-homologous end-joining of DNA double strand breaks in the yeast Saccharomyces cerevisiae.Nucleic Acids Res.25,743e749.
Amin,N.S.,Holm,C.,1996.In vivo analysis reveals that the interdomain region of the yeast proliferating cell nuclear antigen is important for DNA replication and DNA repair.Genetics 144,479e493.
Andreassen,P.R.,Ho,G.P.H.,D'Andrea,A.D.,2006.DNA damage responses and their many interactions with the replication fork.Carcinogenesis 27,883e892.
Ayyagari,R.,Impellizzeri,K.J.,Yoder,B.L.,Gary,S.L.,Burgers,P.M.,1995.A mutational analysis of the yeast proliferating cell nuclear antigen indicates distinct roles in DNA replication and DNA repair.Mol.Cell.Biol.15,4420e4429.
Ball,L.G.,Xu,X.,Blackwell,S.,Hanna,M.D.,Lambrecht,A.D.,Xiao,W.,2014.The Rad5 helicase activity is dispensable for error-free DNA post-replication repair.DNA Repair 16,74e83.
Blastyak,A.,Pinter,L.,Unk,I.,Prakash,L.,Prakash,S.,Haracska,L.,2007.Yeast Rad5protein required for postreplication repair has a DNA helicase activity specific for replication fork regression.Mol.Cell 28,167e175.
Boiteux,S.,Jinks-Robertson,S.,2013.DNA repair mechanisms and the bypass of DNA damage in Saccharomyces cerevisiae.Genetics 193,1025e1064.
Bonner,W.M.,Redon,C.E.,Dickey,J.S.,Nakamura,A.J.,Sedelnikova,O.A.,Solier,S.,Pommier,Y.,2008.g H2AX and cancer.Nat.Rev.Cancer 8,957e967.
Branzei,D.,Szakal,B.,2016.DNA damage tolerance by recombination:Molecular pathways and DNA structures.DNA Repair 44,68e75.
Chang,D.J.,Cimprich,K.A.,2009.DNA damage tolerance:when it’s OK to make mistakes.Nat.Chem.Biol.5,82e90.
Chen,C.,Merrill,B.J.,Lau,P.J.,Holm,C.,Kolodner,R.D.,1999.Saccharomyces cerevisiae pol30(proliferating cell nuclear antigen)mutations impair replication fidelity and mismatch repair.Mol.Cell.Biol.19,7801e7815.
Chen,S.,Davies,A.A.,Sagan,D.,Ulrich,H.D.,2005.The RING finger ATPase Rad5p of Saccharomyces cerevisiae contributes to DNA double-strand break repair in a ubiquitin-independent manner.Nucleic Acids Res.33,5878e5886.
Choe,K.N.,Moldovan,G.-L.,2017.Forging ahead through darkness:PCNA,still the principal conductor at the replication fork.Mol.Cell 65,380e392.
Choi,K.,Batke,S.,Szakal,B.,Lowther,J.,Hao,F.,Sarangi,P.,Branzei,D.,Ulrich,H.D.,Zhao,X.,2015.Concerted and differential actions of two enzymatic domains underlie Rad5 contributions to DNA damage tolerance.Nucleic Acids Res.43,2666e2677.
Dai,J.,Hyland,E.M.,Yuan,D.S.,Huang,H.,Bader,J.S.,Boeke,J.D.,2008.Probing nucleosome function:a highly versatile library of synthetic histone H3 and H4mutants.Cell 134,1066e1078.
Dieckman,L.M.,Freudenthal,B.D.,Washington,M.T.,2012.PCNA structure and function:insights from structures of PCNA complexes and post-translationally modified PCNA.Subcell.Biochem.62,281e299.
Dieckman,L.M.,Washington,M.T.,2013.PCNA trimer instability inhibits translesion synthesis by DNA polymerase h and by DNA polymerase d.DNA Repair 12,367e376.
Eissenberg,J.C.,Ayyagari,R.,Gomes,X.V.,Burgers,P.M.,1997.Mutations in yeast proliferating cell nuclear antigen define distinct sites for interaction with DNApolymerase delta and DNA polymerase epsilon.Mol.Cell.Biol.17,6367e6378.
Fan,L.,Xiao,W.,2016.The Pol30-K196 residue plays a critical role in budding yeast DNA postreplication repair through interaction with Rad18.DNA Repair 47,42e48.
Freudenthal,B.D.,Gakhar,L.,Ramaswamy,S.,Washington,M.T.,2010.Structure of monoubiquitinated PCNA and implications for translesion synthesis and DNApolymerase exchange.Nat.Struct.Mol.Biol.17,479e484.
Fukuda,K.,Morioka,H.,Imajou,S.,Ikeda,S.,Ohtsuka,E.,Tsurimoto,T.,1995.Structure-function relationship of the eukaryotic DNA replication factor,proliferating cell nuclear antigen.J.Biol.Chem.270,22527e22534.
Gangavarapu,V.,Haracska,L.,Unk,I.,Johnson,R.E.,Prakash,S.,Prakash,L.,2006.Mms2-Ubc13-dependent and-independent roles of Rad5 ubiquitin ligase in postreplication repair and translesion DNA synthesis in Saccharomyces cerevisiae.Mol.Cell.Biol.26,7783e7790.
Giannattasio,M.,Zwicky,K.,Follonier,C.,Foiani,M.,Lopes,M.,Branzei,D.,2014.Visualization of recombination-mediated damage bypass by template switching.Nat.Struct.Mol.Biol.21,884e892.
Goellner,E.M.,Smith,C.E.,Campbell,C.S.,Hombauer,H.,Desai,A.,Putnam,C.D.,Kolodner,R.D.,2014.PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair.Mol.Cell 55,291e304.
Hishiki,A.,Shimizu,T.,Serizawa,A.,Ohmori,H.,Sato,M.,Hashimoto,H.,2008.Crystallographic study of G178S mutant of human proliferating cell nuclear antigen.Acta Crystallogr.Sect.F Struct.Biol.Cryst.Commun.64,819e821.
Hoege,C.,Pfander,B.,Moldovan,G.-L.,Pyrowolakis,G.,Jentsch,S.,2002.RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO.Nature 419,135e141.
Hoeijmakers,J.H.J.,2009.DNA damage,aging,and cancer.N.Engl.J.Med.361,1475e1485.
Jiang,S.,Liu,Y.,Wang,A.,Qin,Y.,Luo,M.,Wu,Q.,Boeke,J.D.,Dai,J.,2017a.Construction of comprehensive dosage-matching core histone mutant libraries for Saccharomyces cerevisiae.Genetics 207,1263e1273.
Jiang,S.,Liu,Y.,Xu,C.,Wang,Y.,Gong,J.,Shen,Y.,Wu,Q.,Boeke,J.D.,Dai,J.,2017b.Dissecting nucleosome function with a comprehensive histone H2A and H2Bmutant library.G3 7,3857e3866.
Karras,G.I.,Fumasoni,M.,Sienski,G.,Vanoli,F.,Branzei,D.,Jentsch,S.,2013.Noncanonical role of the 9-1-1 clamp in the error-free DNA damage tolerance pathway.Mol.Cell 49,536e546.
Karras,G.I.,Jentsch,S.,2010.The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S phase.Cell 141,255e267.
Kondratick,C.M.,Boehm,E.M.,Dieckman,L.M.,Powers,K.T.,Sanchez,J.C.,Mueting,S.R.,Washington,M.T.,2016.Identification of new mutations at the PCNA subunit interface that block translesion synthesis.PLoS One 11,e0157023.
Kubota,T.,Nishimura,K.,Kanemaki,M.T.,Donaldson,A.D.,2013.The Elg1 replication factor C-like complex functions in PCNA unloading during DNA replication.Mol.Cell 50,273e280.
Kurth,I.,O'Donnell,M.,2013.New insights into replisome fluidity during chromosome replication.Trends Biochem.Sci.38,195e203.
Lambert,S.,Froget,B.,Carr,A.,2007.Arrested replication fork processing:interplay between checkpoints and recombination.DNA Repair 6,1042e1061.
Lau,W.C.Y.,Li,Y.,Zhang,Q.,Huen,M.S.Y.,2015.Molecular architecture of the UbPCNA/Pol h complex bound to DNA.Sci.Rep.5,15759.
Mailand,N.,Gibbs-Seymour,I.,Bekker-Jensen,S.,2013.Regulation of PCNA-protein interactions for genome stability.Nat.Rev.Mol.Cell Biol.14,269e282.
McNally,R.,Bowman,G.D.,Goedken,E.R.,O’Donnell,M.,Kuriyan,J.,2010.Analysis of the role of PCNA-DNA contacts during clamp loading.BMC Struct.Biol.10,3.
Miller,A.,Chen,J.,Takasuka,T.E.,Jacobi,J.L.,Kaufman,P.D.,Irudayaraj,J.M.K.,Kirchmaier,A.L.,2010.Proliferating cell nuclear antigen(PCNA)is required for cell cycle-regulated silent chromatin on replicated and nonreplicated genes.J.Biol.Chem.285,35142e35154.
Minca,E.C.,Kowalski,D.,2010.Multiple Rad5 activities mediate sister chromatid recombination to bypass DNA damage at stalled replication forks.Mol.Cell 38,649e661.
Moldovan,G.-L.,Pfander,B.,Jentsch,S.,2007.PCNA,the maestro of the replication fork.Cell 129,665e679.
Onge,R.P.S.,Mani,R.,Oh,J.,Proctor,M.,Fung,E.,Davis,R.W.,Nislow,C.,Roth,F.P.,Giaever,G.,2007.Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions.Nat.Genet.39,199e206.
Pages,V.,Bresson,A.,Acharya,N.,Prakash,S.,Fuchs,R.P.,Prakash,L.,2008.Requirement of Rad5 for DNA polymerase zeta-dependent translesion synthesis in Saccharomyces cerevisiae.Genetics 180,73e82.
Papouli,E.,Chen,S.,Davies,A.A.,Huttner,D.,Krejci,L.,Sung,P.,Ulrich,H.D.,2005.Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p.Mol.Cell 19,123e133.
Park,J.M.,Yang,S.W.,Yu,K.R.,Ka,S.H.,Lee,S.W.,Seol,J.H.,Jeon,Y.J.,Chung,C.H.,2014.Modification of PCNA by ISG15 plays a crucial role in termination of errorprone translesion DNA synthesis.Mol.Cell 54,626e638.
Pfander,B.,Moldovan,G.-L.,Sacher,M.,Hoege,C.,Jentsch,S.,2005.SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase.Nature 436,428e433.
Pommier,Y.,Redon,C.,Rao,V.A.,Seiler,J.A.,Sordet,O.,Takemura,H.,Antony,S.,Meng,L.,Liao,Z.,Kohlhagen,G.,Zhang,H.,Kohn,K.W.,2003.Repair of and checkpoint response to topoisomerase I-mediated DNA damage.Mutat.Res.532,173e203.
Rozenzhak,S.,Mejía-Ramírez,E.,Williams,J.S.,Schaffer,L.,Hammond,J.A.,Head,S.R.,Russell,P.,2010.Rad3ATR decorates critical chromosomal domains with g H2A to protect genome integrity during S-phase in fission yeast.PLoSGenet.6,e1001032.
Stirling,P.C.,Bloom,M.S.,Solanki-Patil,T.,Smith,S.,Sipahimalani,P.,Li,Z.,Kofoed,M.,Ben-Aroya,S.,Myung,K.,Hieter,P.,2011.The complete spectrum of yeast chromosome instability genes identifies candidate CIN cancer genes and functional roles for ASTRA complex components.PLoS Genet.7,e1002057.
Stoimenov,I.,Helleday,T.,2009.PCNA on the crossroad of cancer.Biochem.Soc.Trans.37,605e613.
Streich Jr.,F.C.,Lima,C.D.,2016.Capturing a substrate in an activated RING E3/E2e SUMO complex.Nature 536,304e308.
Ulrich,H.D.,Jentsch,S.,2000.Two RING finger proteins mediate cooperation between ubiquitin-conjugating enzymes in DNA repair.EMBO J.19.
Vanoli,F.,Fumasoni,M.,Szakal,B.,Maloisel,L.,Branzei,D.,2010.Replication and recombination factors contributing to recombination-dependent bypass of DNAlesions by template switch.PLoS Genet.6,e1001205.
Vijayakumar,S.,Chapados,B.R.,Schmidt,K.H.,Kolodner,R.D.,Tainer,J.A.,Tomkinson,A.E.,2007.The C-terminal domain of yeast PCNA is required for physical and functional interactions with Cdc9 DNA ligase.Nucleic Acids Res.35,1624e1637.
Winzeler,E.A.,1999.Functional characterization of the Saccharomyces cerevisiae genome by gene deletion and parallel analysis.Science 285,901e906.
Xu,X.,Lin,A.,Zhou,C.,Blackwell,S.R.,Zhang,Y.,Wang,Z.,Feng,Q.,Guan,R.,Hanna,M.D.,Chen,Z.,Xiao,W.,2016.Involvement of budding yeast Rad5 in translesion DNA synthesis through physical interaction with Rev1.Nucleic Acids Res.44,5231e5245.
Yuen,K.W.Y.,Warren,C.D.,Chen,O.,Kwok,T.,Hieter,P.,Spencer,F.A.,2007.Systematic genome instability screens in yeast and their potential relevance to cancer.Proc.Natl.Acad.Sci.U.S.A.104,3925e3930.
Zamir,L.,Zaretsky,M.,Fridman,Y.,Ner-Gaon,H.,Rubin,E.,Aharoni,A.,2012.Tight coevolution of proliferating cell nuclear antigen(PCNA)-partner interaction networks in fungi leads to interspecies network incompatibility.Proc.Natl.Acad.Sci.U.S.A.109,E406e E414.
Zhang,Z.,Shibahara,K.,Stillman,B.,2000.PCNA connects DNA replication to epigenetic inheritance in yeast.Nature 408,221e225.
Amin,N.S.,Holm,C.,1996.In vivo analysis reveals that the interdomain region of the yeast proliferating cell nuclear antigen is important for DNA replication and DNA repair.Genetics 144,479e493.
Andreassen,P.R.,Ho,G.P.H.,D'Andrea,A.D.,2006.DNA damage responses and their many interactions with the replication fork.Carcinogenesis 27,883e892.
Ayyagari,R.,Impellizzeri,K.J.,Yoder,B.L.,Gary,S.L.,Burgers,P.M.,1995.A mutational analysis of the yeast proliferating cell nuclear antigen indicates distinct roles in DNA replication and DNA repair.Mol.Cell.Biol.15,4420e4429.
Ball,L.G.,Xu,X.,Blackwell,S.,Hanna,M.D.,Lambrecht,A.D.,Xiao,W.,2014.The Rad5 helicase activity is dispensable for error-free DNA post-replication repair.DNA Repair 16,74e83.
Blastyak,A.,Pinter,L.,Unk,I.,Prakash,L.,Prakash,S.,Haracska,L.,2007.Yeast Rad5protein required for postreplication repair has a DNA helicase activity specific for replication fork regression.Mol.Cell 28,167e175.
Boiteux,S.,Jinks-Robertson,S.,2013.DNA repair mechanisms and the bypass of DNA damage in Saccharomyces cerevisiae.Genetics 193,1025e1064.
Bonner,W.M.,Redon,C.E.,Dickey,J.S.,Nakamura,A.J.,Sedelnikova,O.A.,Solier,S.,Pommier,Y.,2008.g H2AX and cancer.Nat.Rev.Cancer 8,957e967.
Branzei,D.,Szakal,B.,2016.DNA damage tolerance by recombination:Molecular pathways and DNA structures.DNA Repair 44,68e75.
Chang,D.J.,Cimprich,K.A.,2009.DNA damage tolerance:when it’s OK to make mistakes.Nat.Chem.Biol.5,82e90.
Chen,C.,Merrill,B.J.,Lau,P.J.,Holm,C.,Kolodner,R.D.,1999.Saccharomyces cerevisiae pol30(proliferating cell nuclear antigen)mutations impair replication fidelity and mismatch repair.Mol.Cell.Biol.19,7801e7815.
Chen,S.,Davies,A.A.,Sagan,D.,Ulrich,H.D.,2005.The RING finger ATPase Rad5p of Saccharomyces cerevisiae contributes to DNA double-strand break repair in a ubiquitin-independent manner.Nucleic Acids Res.33,5878e5886.
Choe,K.N.,Moldovan,G.-L.,2017.Forging ahead through darkness:PCNA,still the principal conductor at the replication fork.Mol.Cell 65,380e392.
Choi,K.,Batke,S.,Szakal,B.,Lowther,J.,Hao,F.,Sarangi,P.,Branzei,D.,Ulrich,H.D.,Zhao,X.,2015.Concerted and differential actions of two enzymatic domains underlie Rad5 contributions to DNA damage tolerance.Nucleic Acids Res.43,2666e2677.
Dai,J.,Hyland,E.M.,Yuan,D.S.,Huang,H.,Bader,J.S.,Boeke,J.D.,2008.Probing nucleosome function:a highly versatile library of synthetic histone H3 and H4mutants.Cell 134,1066e1078.
Dieckman,L.M.,Freudenthal,B.D.,Washington,M.T.,2012.PCNA structure and function:insights from structures of PCNA complexes and post-translationally modified PCNA.Subcell.Biochem.62,281e299.
Dieckman,L.M.,Washington,M.T.,2013.PCNA trimer instability inhibits translesion synthesis by DNA polymerase h and by DNA polymerase d.DNA Repair 12,367e376.
Eissenberg,J.C.,Ayyagari,R.,Gomes,X.V.,Burgers,P.M.,1997.Mutations in yeast proliferating cell nuclear antigen define distinct sites for interaction with DNApolymerase delta and DNA polymerase epsilon.Mol.Cell.Biol.17,6367e6378.
Fan,L.,Xiao,W.,2016.The Pol30-K196 residue plays a critical role in budding yeast DNA postreplication repair through interaction with Rad18.DNA Repair 47,42e48.
Freudenthal,B.D.,Gakhar,L.,Ramaswamy,S.,Washington,M.T.,2010.Structure of monoubiquitinated PCNA and implications for translesion synthesis and DNApolymerase exchange.Nat.Struct.Mol.Biol.17,479e484.
Fukuda,K.,Morioka,H.,Imajou,S.,Ikeda,S.,Ohtsuka,E.,Tsurimoto,T.,1995.Structure-function relationship of the eukaryotic DNA replication factor,proliferating cell nuclear antigen.J.Biol.Chem.270,22527e22534.
Gangavarapu,V.,Haracska,L.,Unk,I.,Johnson,R.E.,Prakash,S.,Prakash,L.,2006.Mms2-Ubc13-dependent and-independent roles of Rad5 ubiquitin ligase in postreplication repair and translesion DNA synthesis in Saccharomyces cerevisiae.Mol.Cell.Biol.26,7783e7790.
Giannattasio,M.,Zwicky,K.,Follonier,C.,Foiani,M.,Lopes,M.,Branzei,D.,2014.Visualization of recombination-mediated damage bypass by template switching.Nat.Struct.Mol.Biol.21,884e892.
Goellner,E.M.,Smith,C.E.,Campbell,C.S.,Hombauer,H.,Desai,A.,Putnam,C.D.,Kolodner,R.D.,2014.PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair.Mol.Cell 55,291e304.
Hishiki,A.,Shimizu,T.,Serizawa,A.,Ohmori,H.,Sato,M.,Hashimoto,H.,2008.Crystallographic study of G178S mutant of human proliferating cell nuclear antigen.Acta Crystallogr.Sect.F Struct.Biol.Cryst.Commun.64,819e821.
Hoege,C.,Pfander,B.,Moldovan,G.-L.,Pyrowolakis,G.,Jentsch,S.,2002.RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO.Nature 419,135e141.
Hoeijmakers,J.H.J.,2009.DNA damage,aging,and cancer.N.Engl.J.Med.361,1475e1485.
Jiang,S.,Liu,Y.,Wang,A.,Qin,Y.,Luo,M.,Wu,Q.,Boeke,J.D.,Dai,J.,2017a.Construction of comprehensive dosage-matching core histone mutant libraries for Saccharomyces cerevisiae.Genetics 207,1263e1273.
Jiang,S.,Liu,Y.,Xu,C.,Wang,Y.,Gong,J.,Shen,Y.,Wu,Q.,Boeke,J.D.,Dai,J.,2017b.Dissecting nucleosome function with a comprehensive histone H2A and H2Bmutant library.G3 7,3857e3866.
Karras,G.I.,Fumasoni,M.,Sienski,G.,Vanoli,F.,Branzei,D.,Jentsch,S.,2013.Noncanonical role of the 9-1-1 clamp in the error-free DNA damage tolerance pathway.Mol.Cell 49,536e546.
Karras,G.I.,Jentsch,S.,2010.The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S phase.Cell 141,255e267.
Kondratick,C.M.,Boehm,E.M.,Dieckman,L.M.,Powers,K.T.,Sanchez,J.C.,Mueting,S.R.,Washington,M.T.,2016.Identification of new mutations at the PCNA subunit interface that block translesion synthesis.PLoS One 11,e0157023.
Kubota,T.,Nishimura,K.,Kanemaki,M.T.,Donaldson,A.D.,2013.The Elg1 replication factor C-like complex functions in PCNA unloading during DNA replication.Mol.Cell 50,273e280.
Kurth,I.,O'Donnell,M.,2013.New insights into replisome fluidity during chromosome replication.Trends Biochem.Sci.38,195e203.
Lambert,S.,Froget,B.,Carr,A.,2007.Arrested replication fork processing:interplay between checkpoints and recombination.DNA Repair 6,1042e1061.
Lau,W.C.Y.,Li,Y.,Zhang,Q.,Huen,M.S.Y.,2015.Molecular architecture of the UbPCNA/Pol h complex bound to DNA.Sci.Rep.5,15759.
Mailand,N.,Gibbs-Seymour,I.,Bekker-Jensen,S.,2013.Regulation of PCNA-protein interactions for genome stability.Nat.Rev.Mol.Cell Biol.14,269e282.
McNally,R.,Bowman,G.D.,Goedken,E.R.,O’Donnell,M.,Kuriyan,J.,2010.Analysis of the role of PCNA-DNA contacts during clamp loading.BMC Struct.Biol.10,3.
Miller,A.,Chen,J.,Takasuka,T.E.,Jacobi,J.L.,Kaufman,P.D.,Irudayaraj,J.M.K.,Kirchmaier,A.L.,2010.Proliferating cell nuclear antigen(PCNA)is required for cell cycle-regulated silent chromatin on replicated and nonreplicated genes.J.Biol.Chem.285,35142e35154.
Minca,E.C.,Kowalski,D.,2010.Multiple Rad5 activities mediate sister chromatid recombination to bypass DNA damage at stalled replication forks.Mol.Cell 38,649e661.
Moldovan,G.-L.,Pfander,B.,Jentsch,S.,2007.PCNA,the maestro of the replication fork.Cell 129,665e679.
Onge,R.P.S.,Mani,R.,Oh,J.,Proctor,M.,Fung,E.,Davis,R.W.,Nislow,C.,Roth,F.P.,Giaever,G.,2007.Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions.Nat.Genet.39,199e206.
Pages,V.,Bresson,A.,Acharya,N.,Prakash,S.,Fuchs,R.P.,Prakash,L.,2008.Requirement of Rad5 for DNA polymerase zeta-dependent translesion synthesis in Saccharomyces cerevisiae.Genetics 180,73e82.
Papouli,E.,Chen,S.,Davies,A.A.,Huttner,D.,Krejci,L.,Sung,P.,Ulrich,H.D.,2005.Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p.Mol.Cell 19,123e133.
Park,J.M.,Yang,S.W.,Yu,K.R.,Ka,S.H.,Lee,S.W.,Seol,J.H.,Jeon,Y.J.,Chung,C.H.,2014.Modification of PCNA by ISG15 plays a crucial role in termination of errorprone translesion DNA synthesis.Mol.Cell 54,626e638.
Pfander,B.,Moldovan,G.-L.,Sacher,M.,Hoege,C.,Jentsch,S.,2005.SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase.Nature 436,428e433.
Pommier,Y.,Redon,C.,Rao,V.A.,Seiler,J.A.,Sordet,O.,Takemura,H.,Antony,S.,Meng,L.,Liao,Z.,Kohlhagen,G.,Zhang,H.,Kohn,K.W.,2003.Repair of and checkpoint response to topoisomerase I-mediated DNA damage.Mutat.Res.532,173e203.
Rozenzhak,S.,Mejía-Ramírez,E.,Williams,J.S.,Schaffer,L.,Hammond,J.A.,Head,S.R.,Russell,P.,2010.Rad3ATR decorates critical chromosomal domains with g H2A to protect genome integrity during S-phase in fission yeast.PLoSGenet.6,e1001032.
Stirling,P.C.,Bloom,M.S.,Solanki-Patil,T.,Smith,S.,Sipahimalani,P.,Li,Z.,Kofoed,M.,Ben-Aroya,S.,Myung,K.,Hieter,P.,2011.The complete spectrum of yeast chromosome instability genes identifies candidate CIN cancer genes and functional roles for ASTRA complex components.PLoS Genet.7,e1002057.
Stoimenov,I.,Helleday,T.,2009.PCNA on the crossroad of cancer.Biochem.Soc.Trans.37,605e613.
Streich Jr.,F.C.,Lima,C.D.,2016.Capturing a substrate in an activated RING E3/E2e SUMO complex.Nature 536,304e308.
Ulrich,H.D.,Jentsch,S.,2000.Two RING finger proteins mediate cooperation between ubiquitin-conjugating enzymes in DNA repair.EMBO J.19.
Vanoli,F.,Fumasoni,M.,Szakal,B.,Maloisel,L.,Branzei,D.,2010.Replication and recombination factors contributing to recombination-dependent bypass of DNAlesions by template switch.PLoS Genet.6,e1001205.
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