Abstract
We isolated a pol inhibitor from the cultured mycelia extract of a fungal strain isolated from natural salt from a sea salt pan in Australia, which was identified as 3-O-methylfunicone by spectroscopic analyses. This compound selectively inhibited the activities of mammalian Y-family DNA polymerases (pols) (i.e., pols η, ι and κ). Among these pols, human pol κ activity was most strongly inhibited, with an IC50 value of 12.5 μM. On the other hand, the compound barely influenced the activities of the other families of mammalian pols, such as A-family (i.e., pol γ), B-family (i.e., pols α, δ and ɛ) or X-family (i.e., pols β, λ and terminal deoxynucleotidyl transferase), and showed no effect on the activities of fish pol δ, plant pols, prokaryotic pols and other DNA metabolic enzymes, such as calf primase of pol α, human immunodeficiency virus type-1 (HIV-1) reverse transcriptase, human telomerase, T7 RNA polymerase, mouse IMP dehydrogenase (type II), human topoisomerases I and II, T4 polynucleotide kinase or bovine deoxyribonuclease I. This compound also suppressed the growth of two cultured human cancer cell lines, HCT116 (colon carcinoma cells) and HeLa (cervix carcinoma cells), and UV-treated HeLa cells exhibited lower clonogenic survival in the presence of inhibitor.
Highlights
We have long been interested in the integrity of the genome of eukaryotes and its relation to cell differentiation
The 19 isolated and purified fungal strains from Australian sea salt were cultured, and each cultured mycelium was extracted with chloroform/methanol (v/v 1:1)
When activated DNA (i.e., DNA digested by bovine deoxyribonuclease I [DNase I]) and dNTP was used as the DNA template-primer and nucleotide substrate instead of synthesized DNA [i.e., poly(dA)/oligo(dT)18] and deoxythymidine 5'-triphosphate (dTTP), respectively, the inhibitory effects of the compound were unchanged
Summary
We have long been interested in the integrity of the genome of eukaryotes and its relation to cell differentiation. DNA replication, recombination and repair in eukaryotes are key systems to maintain these processes [1], and DNA polymerases (pols) have important roles in these. In this regard, we have concentrated our efforts on investigating eukaryotic pols associated with these processes [2]. Eukaryotic cells contain three replicative pols (α, δ and ε), mitochondrial pol γ, and at least eleven non-replicative pols [β, ζ, η, θ, ι, κ, λ, μ, ν, terminal deoxynucleotidyl transferase (TdT) and REV1] [3,4,5]. We isolated fungal strains from Australian natural sea salt, and obtained 19 strains These marine strains were screened, and a fungal strain displayed inhibitory activity against mammalian Y-family pols. 3-O-methylfunicone, and the potential of this compound as an anti-cancer chemotherapy agent is discussed
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