POLD1 variants with demonstrated functional effects

Variant Name Protein domain Catalytic residue Evidence of functional significance in model systems References
Yeast Biochemical assays Mouse cells Human cells Mice
D316G Exo Yes Yes
 16
D316H Exo Yes
D316N Exo Yes Yes
 16
E318A Exo Yes Yes
 24
E318D Exo Yes
E318G Exo Yes
E318K Exo Yes Yes
 19
E318Q Exo Yes Yes
 16
E318V Exo Yes
C319R Exo Yes
 16
C319Y Exo Yes
 16
P327L Exo Yes
 Yes
 18,13
D391N Exo Yes
 11
G395S Exo Yes
 8
Y396S Exo Yes
 16
D402A Exo Yes Yes
 Yes
 Yes
 Yes
 Yes
 1,5,6,7,8,9,21,22,24
D402G Exo Yes Yes
 8
D402H Exo Yes
D402N Exo Yes Yes
 16,8
D402V Exo Yes Yes
 9
D402Y Exo Yes
R423H Exo Yes
 13
D458A Exo Yes
 8
L460R Exo Yes
 23
L474P Exo Yes
 13
S478N Exo Yes
 Yes
 18,20,13
Y511F Exo Yes
 8
D515G Exo Yes
D515N Exo Yes
D515V Exo Yes Yes
 Yes
 9,3,4
D515Y Exo Yes
L606M Pol Yes
 Yes
 17,12,22
R689W Pol Yes
 Yes
 Yes
 2,14,15
D825G Pol Yes
 8
P942L Pol Yes
 11
C1061S Other Yes
 10
C1071S Other Yes
 10
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References

  1. Albertson, T.M., et al. DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice. Proc Natl Acad Sci USA 106, 17101–17104 (2009). https://pubmed.ncbi.nlm.nih.gov/19805137/
  2. Daee, D.L., Mertz, T.M., Shcherbakova, P.V. A cancer-associated DNA polymerase δ variant modeled in yeast causes a catastrophic increase in genomic instability. Proc Natl Acad Sci USA 107, 157-162 (2010). https://pubmed.ncbi.nlm.nih.gov/19966286/
  3. Fazlieva, R. et al. Proofreading exonuclease activity of human DNA polymerase δ and its effects on lesion-bypass DNA synthesis. Nucleic Acids Res 37, 2854–2866 (2009). https://pubmed.ncbi.nlm.nih.gov/19282447/
  4. Fortune, J.M., Stith, C.M., Kissling, G.E., Burgers, P.M.J. & Kunkel, T.A. RPA and PCNA suppress formation of large deletion errors by yeast DNA polymerase δ. Nucleic Acids Res 34, 4335–4341 (2006). https://pubmed.ncbi.nlm.nih.gov/16936322/
  5. Ghodgaonkar, M. M. et al. Phenotypic characterization of missense polymerase-δ mutations using an inducible protein-replacement system. Nat Commun 5, 4990 (2014). pubmed.ncbi.nlm.nih.gov/25241845/
  6. Goldsby, R.E. et al. Defective DNA polymerase-δ proofreading causes cancer susceptibility in mice. Nat Med 7, 638-639 (2001). https://pubmed.ncbi.nlm.nih.gov/11385474/
  7. Goldsby, R.E. et al. High incidence of epithelial cancers in mice deficient for DNA polymerase δ proofreading. Proc Natl Acad Sci USA 99, 15560-15565 (2002). https://pubmed.ncbi.nlm.nih.gov/12429860/
  8. Herr, A. J. et al. Mutator suppression and escape from replication error-induced extinction in yeast. PLoS Genet 7, e1002282 (2011). https://pubmed.ncbi.nlm.nih.gov/22022273/
  9. Jin et al. The 3’ →5’ exonuclease of DNA polymerase δ can substitute for the 5’ flap endonuclease Rad27/Fen1 in processing Okazaki fragments and preventing genome instability. Proc Natl Acad Sci USA 98, 5122-5127 (2001). https://pubmed.ncbi.nlm.nih.gov/11309502/
  10. Kiktev, D. A. et al. The fidelity of DNA replication, particularly on GC-rich templates, is reduced by defects of the Fe–S cluster in DNA polymerase δ. Nucleic Acids Res 49, 5623–5636 (2021). https://pubmed.ncbi.nlm.nih.gov/34019669/
  11. Kokoska, R.J., Stefanovic, L., Demai, J. & Petes, T.D. Increased rates of genomic deletions generated by mutations in the yeast gene encoding DNA polymerase δ or by decreases in the cellular levels of DNA polymerase δ. Mol Cell Biol 20, 7490-7504 (2000). pubmed.ncbi.nlm.nih.gov/11003646/
  12. Li, L., Murphy, K.M., Kanevets, U. & Reha-Krantz, L.J. Sensitivity to phosphonoacetic acid: a new phenotype to probe DNA polymerase δ in Saccharomyces cerevisiae. Genetics 170, 569-580 (2005). https://pubmed.ncbi.nlm.nih.gov/15802517/
  13. Mertz, T.M. Characterization of cancer-associated DNA polymerase δ variants. Ph.D. thesis, University of Nebraska Medical Center (2015). https://digitalcommons.unmc.edu/etd_retro/2093/
  14. Mertz, T.M., Baranovskiy, A.G, Wang, J., Tahirov, T.H. & Shcherbakova, P.V. Nucleotide selectivity defect and mutator phenotype conferred by a colon cancer-associated DNA polymerase δ mutation in human cells. Oncogene 36, 4427-4433 (2017). https://pubmed.ncbi.nlm.nih.gov/28368425/
  15. Mertz, T.M., Sharma, S, Chabes, A. & Shcherbakova, P.V. Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity. Proc Natl Acad Sci USA 112, E2467–E2476 (2015). https://pubmed.ncbi.nlm.nih.gov/25827231/
  16. Murphy, K., Darmawan, H., Schultz, A., da Silva, E.F. & Reha-Krantz, L.J. A method to select for mutator DNA polymerase δs in Saccharomyces cerevisiae. Genome 49, 403–410 (2006). https://pubmed.ncbi.nlm.nih.gov/16699561/
  17. Nick McElhinny, S.A., Stith, C.M., Burgers, P.M.J. & Kunkel, T.A. Inefficient proofreading and biased error rates during inaccurate DNA synthesis by a mutant derivative of Saccharomyces cerevisiae DNA polymerase δ. J Biol Chem 282, 2324–2332 (2007). https://pubmed.ncbi.nlm.nih.gov/17121822/
  18. Oh, D.-Y. et al. POLD1 variants leading to reduced polymerase activity can cause hearing loss without syndromic features. Hum Mutat 41(5):913-920 (2020). https://pubmed.ncbi.nlm.nih.gov/31944473/
  19. Ostroverkhova, D. et al. DNA polymerase ε and δ variants drive mutagenesis in polypurine tracts in human tumors. Cell Rep 43, 113655 (2024) https://pubmed.ncbi.nlm.nih.gov/38219146/
  20. Palles, C. et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 45, 136–144 (2013). https://pubmed.ncbi.nlm.nih.gov/23263490/
  21. Sawant, A., et al. Immune checkpoint blockade delays cancer development and extends survival in DNA polymerase mutator syndromes. Cancer Res 85, 1130-1144 (2025). https://pubmed.ncbi.nlm.nih.gov/39786467/
  22. Schmitt, M.W., Matsumoto, Y. & Loeb, L.A. High fidelity and lesion bypass capability of human DNA polymerase δ. Biochimie 91, 1163–1172 (2009). https://pubmed.ncbi.nlm.nih.gov/19540301/
  23. Shcherbakova lab, unpublished data.
  24. Simon, M., Giot, L. & Faye, G. The 3’ to 5’ exonuclease activity located in the DNA polymerase δ subunit of Saccharomyces cerevisiae is required for accurate replication. EMBO J 10, 2165-2170 (1991). https://pubmed.ncbi.nlm.nih.gov/1648480/