DNA polymerases

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DNA polymerases

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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DNA polymerases (or DNA-directed DNA polymerases) are enzymes that catalyse the addition of deoxyribonucleotides to replicating DNA strands and they play crucial roles in the processes that repair different types of DNA damage.

Enzymes

3310

DNA polymerase beta Show summary »« Hide summary

Target Id

3231

Nomenclature

DNA polymerase beta

Genes

POLB (Hs), Polb (Mm), Polb (Rn)

Ensembl ID

ENSG00000070501 (Hs), ENSMUSG00000031536 (Mm), ENSRNOG00000019150 (Rn)

UniProtKB AC

P06746 (Hs), Q8K409 (Mm), P06766 (Rn)

EC number

2.7.7.7

Inhibitors

oleanolic acid pIC₅₀ 5.6 [2]

Comment

DNA polymerase beta plays a key role in the DNA base-excision repair (BER) process. Its inhibition is being explored for potential to exploit synthetic lethality (SL) as a targeted anticancer strategy, in malignancies with defects in their DNA repair pathways [5].

DNA polymerase gamma, catalytic subunit Show summary »« Hide summary

Target Id

3310

Nomenclature

DNA polymerase gamma, catalytic subunit

Previous and unofficial names

POLγ | POLG1 | POLGA | polymerase (DNA directed), gamma

Genes

POLG (Hs), Polg (Mm), Polg (Rn)

Ensembl ID

ENSG00000140521 (Hs), ENSMUSG00000039176 (Mm), ENSRNOG00000032293 (Rn)

UniProtKB AC

P54098 (Hs), DPOG1_RAT (Rn)

Ligands

PZL-A (Binding) (Binds at the POLG/POLG2 interface) [6]

Comment

POLG encodes the catalytic subunit of the heterotrimeric mitochondrial DNA polymerase complex (mtDNA polymerase). The holoenzyme consists of 1 POLG subunit and two accessory subunits that are encoded by POLG2. The enzyme is a potential therapeutic target for diseases that are caused by defective mtDNA polymerase activity [6].

DNA polymerase theta Show summary »« Hide summary

Target Id

3230

Nomenclature

DNA polymerase theta

Previous and unofficial names

POLH | polymerase (DNA directed), theta | polymerase (DNA) theta | POLθ

Genes

POLQ (Hs), Polq (Mm), Polq (Rn)

Ensembl ID

ENSG00000051341 (Hs), ENSMUSG00000034206 (Mm), ENSRNOG00000002471 (Rn)

UniProtKB AC

O75417 (Hs), Q8CGS6 (Mm)

EC number

2.7.7.7

Inhibitors

RP-6685 pIC₅₀ 8.2 [1]

ART812 pIC₅₀ 8.1 [4]

ART558 pIC₅₀ 8.1 [4]

Comment

POLθ is the only eukaryotic polymerase with a helicase domain, in addition to its polymerase domain. POLθ-mediated end-joining (TMEJ) is a component of the process of DNA double-strand break (DSB) repair known as microhomology-mediated end-joining (MMEJ), that mammalian cells employ to eliminate cytotoxic DSBs in replicating cells. TMEJ is an alternative DSB repair mechanism that is deployed when canonical DNA repair pathways (such as nonhomologous end-joining/NHEJ and homologous recombination/HR) are compromised by mutations in crucial genes such as BRCA1 and BRCA2. POLθ is being evaluated as an oncology drug target, for potential to exploit synthetic lethality (SL) as a targeted anticancer strategy, in malignancies with defects in NHEJ and/or HR. Inhibition of POLθ's helicase and polymerase domains is being explored [3].

References

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1. Bubenik M, Mader P, Mochirian P, Vallée F, Clark J, Truchon JF, Perryman AL, Pau V, Kurinov I, Zahn KE et al.. (2022) Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ. J Med Chem, 65 (19): 13198-13215. [PMID:36126059]

2. Gao Z, Maloney DJ, Dedkova LM, Hecht SM. (2008) Inhibitors of DNA polymerase beta: activity and mechanism. Bioorg Med Chem, 16 (8): 4331-40. [PMID:18343122]

3. Pismataro MC, Astolfi A, Barreca ML, Pacetti M, Schenone S, Bandiera T, Carbone A, Massari S. (2023) Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer Therapy. J Med Chem, 66 (10): 6498-6522. [PMID:37134182]

4. Stockley ML, Ferdinand A, Benedetti G, Blencowe P, Boyd SM, Calder M, Charles MD, Edwardes LV, Ekwuru T, Finch H et al.. (2022) Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta. J Med Chem, 65 (20): 13879-13891. [PMID:36200480]

5. Teng JY, Yang DP, Tang C, Fang HS, Sun HY, Xiang YN, Li XM, Yang F, Xia RX, Fan F et al.. (2023) Targeting DNA polymerase β elicits synthetic lethality with mismatch repair deficiency in acute lymphoblastic leukemia. Leukemia, 37 (6): 1204-1215. [PMID:37095208]

6. Valenzuela S, Zhu X, Macao B, Stamgren M, Geukens C, Charifson PS, Kern G, Hoberg E, Jenninger L, Gruszczyk AV et al.. (2025) Small molecules restore mutant mitochondrial DNA polymerase activity. Nature, [Epub ahead of print]. [PMID:40205042]

How to cite this family page

Database page citation:

DNA polymerases. Accessed on 29/06/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1079.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.