DNA polymerase delta


Replicative polymerase; synthesises DNA at the replication fork. May function on the lagging strand. Requires PCNA for processive DNA synthesis.





Molecular weight


•Number of subunits  varies depending on species


Sc: p125 (Pol3), p55 (Pol31), p40 (Pol32); (1)


Sp: p125 (Pol3/Cdc6), p55 (Cdc1), p54 (Cdc27), p42, p22 (Cdm1 (2)


Mammalian: p125, p50, p68, p12 (3) (4) (5) (6)


Biochemical properties


•DNA polymerase

•3’-5’ exonuclease (proofreading)

• collision release mechanism during okasaki synthesis (7)





•p125 has lxcxe (8) -




•PCNA (9) (10) site- (11) p66 interacts- (12) p12 also interacts (13)

• Mgs1/Rad18/Rad5/Mms2 (genetic) (14)


•Subunit interactions (4) (1)



•Rpa (15)

•Wrn with the 50kDa - (16)

•Rb (8) seems to decrease pol activity

•PCNA (Interaction with 50kDa subunit) (17)

• enhancer of rudimentary (18)

• p21 (19)

• PP1 ( via p68) (20)




• p66 is phosphorylated (21)

• p66 and p12 ubiquitylated (22)



• X ray (23)

Cellular location and expression



•Increase in pold towards the end of replication (24) – associated with fibrous structures. Neutralizing antibodies more effective late. Very little co localization with epsilon.

• p12 rapidly degraded via proteosome in response to UV/replication stress (6)

Other comments

•May function as lagging strand polymerase (25) ; (26) (27) ;  (28)

•Requires PCNA for processivity  eg (29)

•Also involved in DNA repair (30) (31) (32) including BIR (33)

• mutator phenotype (34) (35)

• role in HR (36)


• low levels give fragile site instability (37)


•Deplete in xenopus extracts gives replication defects which look like lagging strand defects (38) , epsilon depletes look like lagging and leading, neither substitute for each other.

• accumulates at stalled forks (39)


•Point mutation in proof reading domain -  viable but more tumours (40)

•Transcriptionally controlled sp1 and p53 (41)

•Suggested to correct pol alpha errors (42)

• point mutant causing tumours in an allele specific manner (43)

• HR function (36)

Revised by


Last edited

13 July 09



1.    Johansson,E., Majka,J. and Burgers,P.M. (2001) Structure of DNA polymerase delta from Saccharomyces cerevisiae. J Biol Chem 276, 43824-43828.

2.    Zuo,S., Gibbs,E., Kelman,Z., Wang,T.S., O'Donnell,M., MacNeill,S.A. and Hurwitz,J. (1997) DNA polymerase delta isolated from Schizosaccharomyces pombe contains five subunits. Proc Natl Acad Sci U S A 94, 11244-11249.

3.    Liu,L., Mo,J., Rodriguez-Belmonte,E.M. and Lee,M.Y. (2000) Identification of a fourth subunit of mammalian DNA polymerase delta. J Biol Chem 275, 18739-18744.

4.    Zuo,S., Bermudez,V., Zhang,G., Kelman,Z. and Hurwitz,J. (2000) Structure and activity associated with multiple forms of Schizosaccharomyces pombe DNA polymerase delta. J Biol Chem 275, 5153-5162.

5.    Podust,V.N., Chang,L.S., Ott,R., Dianov,G.L. and Fanning,E. (2002) Reconstitution of human DNA polymerase delta using recombinant baculoviruses: the p12 subunit potentiates DNA polymerizing activity of the four-subunit enzyme. J Biol Chem 277, 3894-3901.

6.    Zhang,S., Zhou,Y., Trusa,S., Meng,X., Lee,E.Y. and Lee,M.Y. (2007) A novel DNA damage response: rapid degradation of the p12 subunit of dna polymerase delta. J Biol Chem 282, 15330-15340.

7.    Langston,L.D. and O'Donnell,M. (2008) DNA polymerase delta is highly processive with proliferating cell nuclear antigen and undergoes collision release upon completing DNA. J Biol Chem 283, 29522-29531.

8.    Krucher,N.A., Zygmunt,A., Mazloum,N., Tamrakar,S., Ludlow,J.W. and Lee,M.Y. (2000) Interaction of the retinoblastoma protein (pRb) with the catalytic subunit of DNA polymerase delta (p125). Oncogene 19, 5464-5470.

9.    O'Day,C.L., Burgers,P.M. and Taylor,J.S. (1992) PCNA-induced DNA synthesis past cis-syn and trans-syn-I thymine dimers by calf thymus DNA polymerase delta in vitro. Nucleic Acids Res 20, 5403-5406.

10.  Brown,W.C. and Campbell,J.L. (1993) Interaction of proliferating cell nuclear antigen with yeast DNA polymerase delta. J Biol Chem 268, 21706-21710.

11.  Zhang,S.J., Zeng,X.R., Zhang,P., Toomey,N.L., Chuang,R.Y., Chang,L.S. and Lee,M.Y. (1995) A conserved region in the amino terminus of DNA polymerase delta is involved in proliferating cell nuclear antigen binding. J Biol Chem 270, 7988-7992.

12.  Ducoux,M., Urbach,S., Baldacci,G., Hubscher,U., Koundrioukoff,S., Christensen,J. and Hughes,P. (2001) Mediation of proliferating cell nuclear antigen (PCNA)-dependent DNA replication through a conserved p21(Cip1)-like PCNA-binding motif present in the third subunit of human DNA polymerase delta. J Biol Chem 276, 49258-49266.

13.  Li,H., Xie,B., Zhou,Y., Rahmeh,A., Trusa,S., Zhang,S., Gao,Y., Lee,E.Y. and Lee,M.Y. (2006) Functional roles of p12, the fourth subunit of human DNA polymerase delta. J Biol Chem 281, 14748-14755.

14.  Vijeh Motlagh,N.D., Seki,M., Branzei,D. and Enomoto,T. (2006) Mgs1 and Rad18/Rad5/Mms2 are required for survival of Saccharomyces cerevisiae mutants with novel temperature/cold sensitive alleles of the DNA polymerase delta subunit, Pol31. DNA Repair (Amst) 5, 1459-1474.

15.  Mo,J., Liu,L., Leon,A., Mazloum,N. and Lee,M.Y. (2000) Evidence that DNA polymerase delta isolated by immunoaffinity chromatography exhibits high-molecular weight characteristics and is associated with the KIAA0039 protein and RPA. Biochemistry 39, 7245-7254.

16.  Szekely,A.M., Chen,Y.H., Zhang,C., Oshima,J. and Weissman,S.M. (2000) Werner protein recruits DNA polymerase delta to the nucleolus. Proc Natl Acad Sci U S A 97, 11365-11370.

17.  Lu,X., Tan,C.K., Zhou,J.Q., You,M., Carastro,L.M., Downey,K.M. and So,A.G. (2002) Direct interaction of proliferating cell nuclear antigen with the small subunit of DNA polymerase delta. J Biol Chem 277, 24340-24345.

18.  Smyk,A., Szuminska,M., Uniewicz,K.A., Graves,L.M. and Kozlowski,P. (2006) Human enhancer of rudimentary is a molecular partner of PDIP46/SKAR, a protein interacting with DNA polymerase delta and S6K1 and regulating cell growth. FEBS J 273, 4728-4741.

19.  Li,H., Xie,B., Rahmeh,A., Zhou,Y. and Lee,M.Y. (2006) Direct interaction of p21 with p50, the small subunit of human DNA polymerase delta. Cell Cycle 5, 428-436.

20.  Gao,Y., Zhou,Y., Xie,B., Zhang,S., Rahmeh,A., Huang,H.S., Lee,M.Y. and Lee,E.Y. (2008) Protein phosphatase-1 is targeted to DNA polymerase delta via an interaction with the p68 subunit. Biochemistry 47, 11367-11376.

21.  Lemmens,L., Urbach,S., Prudent,R., Cochet,C., Baldacci,G. and Hughes,P. (2008) Phosphorylation of the C subunit (p66) of human DNA polymerase delta. Biochem Biophys Res Commun 367, 264-270.

22.  Liu,G. and Warbrick,E. (2006) The p66 and p12 subunits of DNA polymerase delta are modified by ubiquitin and ubiquitin-like proteins. Biochem Biophys Res Commun 349, 360-366.

23.  Baranovskiy,A.G., Babayeva,N.D., Liston,V.G., Rogozin,I.B., Koonin,E.V., Pavlov,Y.I., Vassylyev,D.G. and Tahirov,T.H. (2008) X-ray structure of the complex of regulatory subunits of human DNA polymerase delta. Cell Cycle 7, 3026-3036.

24.  Rytkonen,A.K., Vaara,M., Nethanel,T., Kaufmann,G., Sormunen,R., Laara,E., Nasheuer,H.P., Rahmeh,A., Lee,M.Y., Syvaoja,J.E. and Pospiech,H. (2006) Distinctive activities of DNA polymerases during human DNA replication. FEBS J 273, 2984-3001.

25.  Jin,Y.H., Obert,R., Burgers,P.M., Kunkel,T.A., Resnick,M.A. and Gordenin,D.A. (2001) The 3'-->5' exonuclease of DNA polymerase delta can substitute for the 5' flap endonuclease Rad27/Fen1 in processing Okazaki fragments and preventing genome instability. Proc Natl Acad Sci U S A 98, 5122-5127.

26.  Ayyagari,R., Gomes,X.V., Gordenin,D.A. and Burgers,P.M. (2003) Okazaki fragment maturation in yeast. I. Distribution of functions between FEN1 AND DNA2. J Biol Chem278, 1618-1625.

27.  Jin,Y.H., Ayyagari,R., Resnick,M.A., Gordenin,D.A. and Burgers,P.M. (2003) Okazaki fragment maturation in yeast. II. Cooperation between the polymerase and 3'-5'-exonuclease activities of Pol delta in the creation of a ligatable nick. J Biol Chem 278, 1626-1633.

28.  Garg,P., Stith,C.M., Sabouri,N., Johansson,E. and Burgers,P.M. (2004) Idling by DNA polymerase delta maintains a ligatable nick during lagging-strand DNA replication. Genes Dev 18, 2764-2773.

29.  Garg,P. and Burgers,P.M. (2005) DNA polymerases that propagate the eukaryotic DNA replication fork. Crit Rev Biochem Mol Biol 40, 115-128.

30.  Huang,M.E., de Calignon,A., Nicolas,A. and Galibert,F. (2000) POL32, a subunit of the Saccharomyces cerevisiae DNA polymerase delta, defines a link between DNA replication and the mutagenic bypass repair pathway. Curr Genet 38, 178-187.

31.  MacNeill,S.A., Moreno,S., Reynolds,N., Nurse,P. and Fantes,P.A. (1996) The fission yeast Cdc1 protein, a homologue of the small subunit of DNA polymerase delta, binds to Pol3 and Cdc27. EMBO J 15, 4613-4628.

32.  Torres-Ramos,C.A., Prakash,S. and Prakash,L. (1997) Requirement of yeast DNA polymerase delta in post-replicational repair of UV-damaged DNA. J Biol Chem 272, 25445-25448.

33.  Lydeard,J.R., Jain,S., Yamaguchi,M. and Haber,J.E. (2007) Break-induced replication and telomerase-independent telomere maintenance require Pol32. Nature448, 820-823.

34.  Venkatesan,R.N., Hsu,J.J., Lawrence,N.A., Preston,B.D. and Loeb,L.A. (2006) Mutator phenotypes caused by substitution at a conserved motif A residue in eukaryotic DNA polymerase delta. J Biol Chem 281, 4486-4494.

35.  Nick McElhinny,S.A., Stith,C.M., Burgers,P.M. and Kunkel,T.A. (2007) Inefficient proofreading and biased error rates during inaccurate DNA synthesis by a mutant derivative of Saccharomyces cerevisiae DNA polymerase delta. J Biol Chem 282, 2324-2332.

36.  Maloisel,L., Fabre,F. and Gangloff,S. (2008) DNA polymerase delta is preferentially recruited during homologous recombination to promote heteroduplex DNA extension. Mol Cell Biol 28, 1373-1382.

37.  Lemoine,F.J., Degtyareva,N.P., Kokoska,R.J. and Petes,T.D. (2008) Reduced levels of DNA polymerase delta induce chromosome fragile site instability in yeast. Mol Cell Biol 28, 5359-5368.

38.  Fukui,T., Yamauchi,K., Muroya,T., Akiyama,M., Maki,H., Sugino,A. and Waga,S. (2004) Distinct roles of DNA polymerases delta and epsilon at the replication fork in Xenopus egg extracts. Genes Cells 9, 179-191.

39.  Sasakawa,N., Fukui,T. and Waga,S. (2006) Accumulation of FFA-1, the Xenopus homolog of Werner helicase, and DNA polymerase delta on chromatin in response to replication fork arrest. J Biochem 140, 95-103.

40.  Goldsby,R.E., Lawrence,N.A., Hays,L.E., Olmsted,E.A., Chen,X., Singh,M. and Preston,B.D. (2001) Defective DNA polymerase-delta proofreading causes cancer susceptibility in mice. Nat Med 7(6), 638-639.

41.  Li,B. and Lee,M.Y. (2001) Transcriptional regulation of the human DNA polymerase delta catalytic subunit gene POLD1 by p53 tumor suppressor and Sp1. J Biol Chem276, 29729-29739.

42.  Pavlov,Y.I., Frahm,C., Nick McElhinny,S.A., Niimi,A., Suzuki,M. and Kunkel,T.A. (2006) Evidence that errors made by DNA polymerase alpha are corrected by DNA polymerase delta. Curr Biol 16, 202-207.

43.  Venkatesan,R.N., Treuting,P.M., Fuller,E.D., Goldsby,R.E., Norwood,T.H., Gooley,T.A., Ladiges,W.C., Preston,B.D. and Loeb,L.A. (2007) Mutation at the polymerase active site of mouse DNA polymerase delta increases genomic instability and accelerates tumorigenesis. Mol Cell Biol 27, 7669-7682.