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Review
. 2020 Dec 3;21(23):9226.
doi: 10.3390/ijms21239226.

Focus on DNA Glycosylases-A Set of Tightly Regulated Enzymes with a High Potential as Anticancer Drug _targets

Fabienne Hans  1 , Muge Senarisoy  1 , Chandini Bhaskar Naidu  1 , Joanna Timmins  1
Affiliations
Review

Focus on DNA Glycosylases-A Set of Tightly Regulated Enzymes with a High Potential as Anticancer Drug _targets

Fabienne Hans et al. Int J Mol Sci. .

Abstract

Cancer is the second leading cause of death with tens of millions of people diagnosed with cancer every year around the world. Most radio- and chemotherapies aim to eliminate cancer cells, notably by causing severe damage to the DNA. However, efficient repair of such damage represents a common mechanism of resistance to initially effective cytotoxic agents. Thus, development of new generation anticancer drugs that _target DNA repair pathways, and more particularly the base excision repair (BER) pathway that is responsible for removal of damaged bases, is of growing interest. The BER pathway is initiated by a set of enzymes known as DNA glycosylases. Unlike several downstream BER enzymes, DNA glycosylases have so far received little attention and the development of specific inhibitors of these enzymes has been lagging. Yet, dysregulation of DNA glycosylases is also known to play a central role in numerous cancers and at different stages of the disease, and thus inhibiting DNA glycosylases is now considered a valid strategy to eliminate cancer cells. This review provides a detailed overview of the activities of DNA glycosylases in normal and cancer cells, their modes of regulation, and their potential as anticancer drug _targets.

Keywords: DNA glycosylases; base excision repair; cancer; drug resistance; inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram illustrating the steps and enzymes involved in the base excision repair (BER) pathway. Representative structures of the different superfamilies (SF) of DNA glycosylases (SF1, α/β fold family, red; SF2, helix-hairpin-helix (HhH) family, purple; SF3, 3-methyl-purine glycosylase (MPG) family, green; SF4, helix-two-turn-helix (H2TH) family, blue) responsible for recognition and removal of damaged bases are shown. After cleavage of the damaged strand by an apurinic/apyrimidinic (AP) endonuclease, APE1, or by the AP lyase activity of bifunctional DNA glycosylases, downstream BER enzymes together with several cofactors (listed in brown) prepare the damaged site for de novo synthesis using one of two sub-pathways: short-patch or long-patch repair. DNA glycosylases are tightly regulated at the gene, mRNA, and protein levels by a set of regulatory systems (listed in orange). UNG1/2: uracil-N glycosylase 1 or 2; SMUG1: single-strand-specific monofunctional uracil DNA glycosylase 1; TDG: thymine DNA glycosylase; MBD4: methyl-CpG-binding protein 4; MUTYH: MutY homolog DNA glycosylase; OGG1: 8-oxo-G DNA glycosylase 1; NTH1: endonuclease III-like 1; NEIL1-3: endonuclease VIII-like 1-3.
Figure 2
Figure 2
mRNA expression profiles of six representative DNA glycosylase genes in various carcinomas. mRNA expression profiles of UNG (A), SMUG1 (B), NTH1 (C), OGG1 (D), MPG (E) and NEIL3 (F). Data were extracted from the cBio Cancer Genomics Portal [140] by computing the expression of an individual gene in a tumor sample (z-score) relative to the gene’s expression in the normal sample. Samples with expression z-scores >2 or <−2 (indicated with dotted lines) in any queried gene are considered altered. mRNA expression levels are organized according to the copy-number level per gene: Deep deletion (dark blue) indicates a deep loss, possibly a homozygous deletion; shallow deletion (sky blue) indicates a shallow loss, possibly a heterozygous deletion; diploid (gray); gain (pink) indicates a low-level gain (a few additional copies, often broad); and amplification (red) indicates a high-level amplification (more copies, often focal). Cancer types: Bladder urothelial carcinoma (bladder; N = 404), colorectal adenocarcinoma (colorectal; N = 590), esophageal squamous cell carcinoma (esophageal; N = 94), hepatocellular carcinoma (liver; N = 358), invasive breast carcinoma (breast; N = 1068), non-small cell lung cancer (lung; N = 991), and prostate adenocarcinoma (prostate; N = 488).
Figure 3
Figure 3
Schematic diagrams illustrating the different fluorescence-based assays developed over the past decade for high-throughput screening (HTS) of chemical libraries for the selection of inhibitors of either the AP-lyase activity [193] (A), the DNA glycosylase activity [197] (B) of DNA glycosylases, or of the interaction interface (C) between a DNA glycosylase (here, NTH1) and its cellular partner (YB1) [162]. FRET: Förster resonance energy transfer. In (A), X denotes a damaged base processed by DNA glycosylases. Cleavage by the AP lyase activity results in the release of the fluorophore-labeled lesion-containing strand and fluorescence emission (red F). In (B), release of a modified 8-oxo-G base (oG) linked to a quencher that specifically quenches the highly fluorescent DNA base analogue, tCo, covalently bound to the neighboring base, leads to fluorescence emission (red C). In (C), NTH1-YB1 complex formation is associated with high FRET levels, which are significantly reduced by inhibitors (red wedge) of the PPI interface.
Figure 4
Figure 4
Identification of specific inhibitors of human OGG1. (A) Crystal structure of human OGG1 crosslinked to 8-oxo-G containing dsDNA (PDB: 6W0M; [201]). (B) Crystal structure of human OGG1 bound to an active site-specific inhibitor, TH5487 (PDB 6RLW), represented in ball and sticks and as a transparent mesh. (C) Chemical structure of the highly specific OGG1 inhibitor selected by Tahara and colleagues [197], SU0268. (D) Chemical structure of the dual inhibitor, SU0383, which efficiently blocks both MTH1 and OGG1 activities [202].
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