6s1n

Structural highlights

Disease

[DPOD1_HUMAN] Mandibular hypoplasia-deafness-progeroid features-lipodystrophy syndrome;Polymerase proofreading-related adenomatous polyposis. Disease susceptibility is associated with variations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

[DPOD4_HUMAN] As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair. Within this complex, increases the rate of DNA synthesis and decreases fidelity by regulating POLD1 polymerase and proofreading 3' to 5' exonuclease activity (PubMed:16510448, PubMed:19074196, PubMed:20334433). Pol-delta4 participates in Okazaki fragment processing, through both the short flap pathway, as well as a nick translation system (PubMed:24035200). Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR), a mechanism that may induce segmental genomic duplications of up to 200 kb (PubMed:24310611). Involved in Pol-delta4 translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites (PubMed:19074196). Its degradation in response to DNA damage is required for the inhibition of fork progression and cell survival (PubMed:24022480).^{[1] [2] [3] [4] [5] [6]} [DPOD1_HUMAN] As the catalytic component of the trimeric (Pol-delta3 complex) and tetrameric DNA polymerase delta complexes (Pol-delta4 complex), plays a crucial role in high fidelity genome replication, including in lagging strand synthesis, and repair. Exhibits both DNA polymerase and 3'- to 5'-exonuclease activities (PubMed:16510448, PubMed:19074196, PubMed:20334433, PubMed:24035200, PubMed:24022480). Requires the presence of accessory proteins POLD2, POLD3 and POLD4 for full activity. Depending upon the absence (Pol-delta3) or the presence of POLD4 (Pol-delta4), displays differences in catalytic activity. Most notably, expresses higher proofreading activity in the context of Pol-delta3 compared with that of Pol-delta4 (PubMed:19074196, PubMed:20334433). Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may be better suited to fulfill this task, exhibiting near-absence of strand displacement activity compared to Pol-delta4 and stalling on encounter with the 5'-blocking oligonucleotides. Pol-delta3 idling process may avoid the formation of a gap, while maintaining a nick that can be readily ligated (PubMed:24035200). Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation (PubMed:20227374). Under conditions of DNA replication stress, in the presence of POLD3 and POLD4, may catalyze the repair of broken replication forks through break-induced replication (BIR) (PubMed:24310611). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites (PubMed:19074196).^{[7] [8] [9] [10] [11] [12] [13]} [DPOD3_HUMAN] Required for optimal DNA polymerase delta activity.^{[14] [15] [16]} [DPOD2_HUMAN] The function of the small subunit is not yet clear. [PCNA_HUMAN] Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways. Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion.^{[17] [18]}

References

1. ↑ Li H, Xie B, Zhou Y, Rahmeh A, Trusa S, Zhang S, Gao Y, Lee EY, Lee MY. Functional roles of p12, the fourth subunit of human DNA polymerase delta. J Biol Chem. 2006 May 26;281(21):14748-55. Epub 2006 Feb 28. PMID:16510448 doi:http://dx.doi.org/10.1074/jbc.M600322200
2. ↑ Meng X, Zhou Y, Zhang S, Lee EY, Frick DN, Lee MY. DNA damage alters DNA polymerase delta to a form that exhibits increased discrimination against modified template bases and mismatched primers. Nucleic Acids Res. 2009 Feb;37(2):647-57. doi: 10.1093/nar/gkn1000. Epub 2008 Dec, 11. PMID:19074196 doi:http://dx.doi.org/10.1093/nar/gkn1000
3. ↑ Meng X, Zhou Y, Lee EY, Lee MY, Frick DN. The p12 subunit of human polymerase delta modulates the rate and fidelity of DNA synthesis. Biochemistry. 2010 May 4;49(17):3545-54. doi: 10.1021/bi100042b. PMID:20334433 doi:http://dx.doi.org/10.1021/bi100042b
4. ↑ Terai K, Shibata E, Abbas T, Dutta A. Degradation of p12 subunit by CRL4Cdt2 E3 ligase inhibits fork progression after DNA damage. J Biol Chem. 2013 Oct 18;288(42):30509-14. doi: 10.1074/jbc.C113.505586. Epub, 2013 Sep 10. PMID:24022480 doi:http://dx.doi.org/10.1074/jbc.C113.505586
5. ↑ Lin SH, Wang X, Zhang S, Zhang Z, Lee EY, Lee MY. Dynamics of enzymatic interactions during short flap human Okazaki fragment processing by two forms of human DNA polymerase delta. DNA Repair (Amst). 2013 Nov;12(11):922-35. doi: 10.1016/j.dnarep.2013.08.008., Epub 2013 Sep 10. PMID:24035200 doi:http://dx.doi.org/10.1016/j.dnarep.2013.08.008
6. ↑ Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E, Helleday T, Haber JE, Iliakis G, Kallioniemi OP, Halazonetis TD. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science. 2014 Jan 3;343(6166):88-91. doi: 10.1126/science.1243211. Epub 2013 Dec , 5. PMID:24310611 doi:http://dx.doi.org/10.1126/science.1243211
7. ↑ Li H, Xie B, Zhou Y, Rahmeh A, Trusa S, Zhang S, Gao Y, Lee EY, Lee MY. Functional roles of p12, the fourth subunit of human DNA polymerase delta. J Biol Chem. 2006 May 26;281(21):14748-55. Epub 2006 Feb 28. PMID:16510448 doi:http://dx.doi.org/10.1074/jbc.M600322200
8. ↑ Meng X, Zhou Y, Zhang S, Lee EY, Frick DN, Lee MY. DNA damage alters DNA polymerase delta to a form that exhibits increased discrimination against modified template bases and mismatched primers. Nucleic Acids Res. 2009 Feb;37(2):647-57. doi: 10.1093/nar/gkn1000. Epub 2008 Dec, 11. PMID:19074196 doi:http://dx.doi.org/10.1093/nar/gkn1000
9. ↑ Ogi T, Limsirichaikul S, Overmeer RM, Volker M, Takenaka K, Cloney R, Nakazawa Y, Niimi A, Miki Y, Jaspers NG, Mullenders LH, Yamashita S, Fousteri MI, Lehmann AR. Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells. Mol Cell. 2010 Mar 12;37(5):714-27. doi: 10.1016/j.molcel.2010.02.009. PMID:20227374 doi:http://dx.doi.org/10.1016/j.molcel.2010.02.009
10. ↑ Meng X, Zhou Y, Lee EY, Lee MY, Frick DN. The p12 subunit of human polymerase delta modulates the rate and fidelity of DNA synthesis. Biochemistry. 2010 May 4;49(17):3545-54. doi: 10.1021/bi100042b. PMID:20334433 doi:http://dx.doi.org/10.1021/bi100042b
11. ↑ Terai K, Shibata E, Abbas T, Dutta A. Degradation of p12 subunit by CRL4Cdt2 E3 ligase inhibits fork progression after DNA damage. J Biol Chem. 2013 Oct 18;288(42):30509-14. doi: 10.1074/jbc.C113.505586. Epub, 2013 Sep 10. PMID:24022480 doi:http://dx.doi.org/10.1074/jbc.C113.505586
12. ↑ Lin SH, Wang X, Zhang S, Zhang Z, Lee EY, Lee MY. Dynamics of enzymatic interactions during short flap human Okazaki fragment processing by two forms of human DNA polymerase delta. DNA Repair (Amst). 2013 Nov;12(11):922-35. doi: 10.1016/j.dnarep.2013.08.008., Epub 2013 Sep 10. PMID:24035200 doi:http://dx.doi.org/10.1016/j.dnarep.2013.08.008
13. ↑ Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E, Helleday T, Haber JE, Iliakis G, Kallioniemi OP, Halazonetis TD. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science. 2014 Jan 3;343(6166):88-91. doi: 10.1126/science.1243211. Epub 2013 Dec , 5. PMID:24310611 doi:http://dx.doi.org/10.1126/science.1243211
14. ↑ Hughes P, Tratner I, Ducoux M, Piard K, Baldacci G. Isolation and identification of the third subunit of mammalian DNA polymerase delta by PCNA-affinity chromatography of mouse FM3A cell extracts. Nucleic Acids Res. 1999 May 15;27(10):2108-14. PMID:10219083
15. ↑ Mo J, Liu L, Leon A, Mazloum N, Lee MY. Evidence that DNA polymerase delta isolated by immunoaffinity chromatography exhibits high-molecular weight characteristics and is associated with the KIAA0039 protein and RPA. Biochemistry. 2000 Jun 20;39(24):7245-54. PMID:10852724
16. ↑ Li H, Xie B, Zhou Y, Rahmeh A, Trusa S, Zhang S, Gao Y, Lee EY, Lee MY. Functional roles of p12, the fourth subunit of human DNA polymerase delta. J Biol Chem. 2006 May 26;281(21):14748-55. Epub 2006 Feb 28. PMID:16510448 doi:http://dx.doi.org/10.1074/jbc.M600322200
17. ↑ Burkovics P, Hajdu I, Szukacsov V, Unk I, Haracska L. Role of PCNA-dependent stimulation of 3'-phosphodiesterase and 3'-5' exonuclease activities of human Ape2 in repair of oxidative DNA damage. Nucleic Acids Res. 2009 Jul;37(13):4247-55. doi: 10.1093/nar/gkp357. Epub 2009, May 13. PMID:19443450 doi:10.1093/nar/gkp357
18. ↑ Motegi A, Liaw HJ, Lee KY, Roest HP, Maas A, Wu X, Moinova H, Markowitz SD, Ding H, Hoeijmakers JH, Myung K. Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks. Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12411-6. Epub 2008 Aug 21. PMID:18719106 doi:0805685105
19. ↑ Lancey C, Tehseen M, Raducanu VS, Rashid F, Merino N, Ragan TJ, Savva CG, Zaher MS, Shirbini A, Blanco FJ, Hamdan SM, De Biasio A. Structure of the processive human Pol delta holoenzyme. Nat Commun. 2020 Feb 28;11(1):1109. doi: 10.1038/s41467-020-14898-6. PMID:32111820 doi:http://dx.doi.org/10.1038/s41467-020-14898-6