POLE 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
D275A Exo Yes
D275E Exo Yes
D275G Exo Yes
D275H Exo Yes
D275N Exo Yes Yes
 1
D275Q Exo Yes
D275V Exo Yes Yes
 Yes
 2,3
D275Y Exo Yes
E277D Exo Yes
E277G Exo Yes
E277K Exo Yes
E277Q Exo Yes
E277V Exo Yes
T278K Exo Yes
 1
P286H Exo Yes
 Yes
 3,19
P286R Exo Yes
 Yes
 Yes
 Yes
 9,12,13,14,19,21
M295R Exo Yes
 11
S297F Exo Yes
 7
N363D Exo Yes
 17
N363K Exo Yes
 Yes
 Yes
 1,10,4
F367S Exo Yes
 Yes
 3,2,19
D368E Exo Yes
D368G Exo Yes
D368N Exo Yes
D368V Exo Yes
D368Y Exo Yes
V411L Exo Yes
 Yes
 Yes
 2,3,14,16,19
L424I Exo Yes
 19
L424V Exo Yes
 Yes
 Yes
 Yes
 2,3,10,16,19
P436R Exo Yes
 3
M444K Exo Yes
 15,7
A456P Exo Yes
 11
Y458F Exo Yes
 4
S459F Exo Yes
 Yes
 Yes
 Yes
 2,3,6,8,19
S461L Exo Yes
 15
S461P Exo Yes
 20
D462A Exo Yes
D462E Exo Yes
D462G Exo Yes
D462H Exo Yes
D462N Exo Yes
D462V Exo Yes
D462Y Exo Yes
A465V Exo Yes
 15
V474I Other Yes
 5
M630I Pol Yes
 18
P696S Pol Yes
 18
E978G Pol Yes
 15
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References

  1. Barbari, S.R. Functional characterization of cancer-associated DNA polymerase ε variants. Ph.D. thesis, University of Nebraska Medical Center (2021). https://digitalcommons.unmc.edu/etd/600/
  2. Barbari, S.R. et al. Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase ε variants at low dNTP levels. Nucleic Acids Res 50, 8023-8040 (2022). https://pubmed.ncbi.nlm.nih.gov/35822874/
  3. Barbari, S.R., Kane, D.P., Moore, E.A. & Shcherbakova, P.V. Functional analysis of cancer-associated DNA polymerase ε variants in Saccharomyces cerevisiae. G3 (Bethesda) 8, 1019-1029 (2018). https://pubmed.ncbi.nlm.nih.gov/29352080/
  4. Dahl, J.M. et al. Probing the mechanisms of two exonuclease domain mutators of DNA polymerase ε. Nucleic Acids Res 50, 962-74 (2022). pubmed.ncbi.nlm.nih.gov/35037018/
  5. Esteban-Jurado, C. et al. POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. Oncotarget, 8, 26732-26743 (2017). https://pubmed.ncbi.nlm.nih.gov/28423643/
  6. Galati, M.A. et al. Cancers from novel Pole-mutant mouse models provide insights into polymerase-mediated hypermutagenesis and immune checkpoint blockade. Cancer Res 80, 5606-5618 (2020). https://pubmed.ncbi.nlm.nih.gov/32938641/
  7. Herzog, M. et al. Mutagenic mechanisms of cancer-associated DNA polymerase ε alleles. Nucleic Acids Res 49, 3919-3931 (2021). pubmed.ncbi.nlm.nih.gov/33764464/
  8. Hodel, K.P. et al. POLE mutation spectra are shaped by the mutant allele identity, its abundance, and mismatch repair status. Mol Cell 78, 1166-1177 (2020). https://pubmed.ncbi.nlm.nih.gov/32497495/
  9. Kane, D.P. & Shcherbakova, P.V. A common cancer-associated DNA polymerase ε mutation causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from loss of proofreading. Cancer Res 74, 1895-901 (2014). pubmed.ncbi.nlm.nih.gov/24525744/
  10. Labrousse, G. et al. The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity. NAR Cancer 5, zcad011 (2023). https://pubmed.ncbi.nlm.nih.gov/36915289/
  11. Lee, M. et al. Homologous recombination repair truncations predict hypermutation in microsatellite stable colorectal and endometrial tumors. Clin Transl Gastroenterol 11, e00149 (2020). https://pubmed.ncbi.nlm.nih.gov/32352724/
  12. Li, H.D. et al. A PoleP286R/+mouse model of endometrial cancer recapitulates high mutational burden and immunotherapy response. JCI Insight 5, e138829 (2020). https://pubmed.ncbi.nlm.nih.gov/32699191/
  13. Li, H.D. et al. Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load. J Clin Invest 128, 4179-4191 (2018). https://pubmed.ncbi.nlm.nih.gov/30124468/
  14. Ma, X. et al. Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity. Nat. Genet. 54, 996-1012 (2022). https://pubmed.ncbi.nlm.nih.gov/35817971/
  15. 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/
  16. 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/
  17. Shcherbakova lab, unpublished data.
  18. Shcherbakova, P.V., Noskov, V.N., Pshenichnov, M.R., Pavlov, Y.I. Base analog 6-N-hydroxylaminopurine mutagenesis in the yeast Saccharomyces cerevisiae is controlled by replicative DNA polymerases. Mutat. Res., 369, 33-44 (1996). https://pubmed.ncbi.nlm.nih.gov/8700180/
  19. Shinbrot, E. et al. Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication. Genome Res 24, 1740-50 (2014). pubmed.ncbi.nlm.nih.gov/25228659/
  20. Shlien, A., et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet 47, 257-262 (2015). https://pubmed.ncbi.nlm.nih.gov/25642631/
  21. Xing, X. et al. A recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme. Nat Commun 10, 374 (2019). pubmed.ncbi.nlm.nih.gov/30670691/