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

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.

TRIM26 Maintains Cell Survival in Response to Oxidative Stress through Regulating DNA Glycosylase Stability

“…A number of studies have demonstrated that the efficiency of the BER pathway is subject to tight control by post-translational modifications, of which ubiquitylation as a mechanism for regulating individual repair protein levels has been increasingly found [ 15 , 16 ]. DNA glycosylases specifically are a target for regulation at both the transcriptional and post-translational level [ 33 ], which avoids the build-up of potentially more toxic BER intermediates. The importance of controlling DNA glycosylase levels is displayed by the altered protein expression observed in several diseases, including neurodegenerative diseases and cancer.…”

Characterization of a Novel Thermostable DNA Lyase Used To Prepare DNA for Next-Generation Sequencing

“…An understanding of the repair efficiency and substrate selectivity of different DNA repair enzymes can reveal vulnerabilities in the genome. Second, DNA repair enzymes are potential pharmacological targets where DNA repair pathway inhibition, coupled with other metabolic deficiencies, could result in selective toxicity. − Third, DNA repair enzymes can serve as valuable reagents for characterizing and quantifying specific types of DNA damage, − identifying the location of specific types of DNA damage at nucleotide resolution, − and for preparing input DNA for next-generation sequencing. − …”

“…Following the generation of an abasic site in a glycosylase activity assay, the DNA cleavage step can be accomplished by the addition of hydroxide or other strand cleavage catalysts. However, such reagents would be added at the end of the glycosylase assay, which would prevent continuous monitoring of glycosylase excision using FRET-based assays. − Alternatively, a glycosylase could be coupled with a bifunctional glycosylase or an apurinic endonuclease such as apurinic/apyrimidinic endonuclease I (APE1). There are two challenges with the latter approach.…”

“…However, glycosylase assays are frequently based upon the cleavage of DNA strands following glycosylase excision of a target base. , DNA strands, labeled with either 32 P or fluorescent tags, can be separated by either gel electrophoresis or HPLC and quantified. While many DNA repair enzymes are bifunctional with the capacity to remove a base from DNA, generate an abasic site, and cleave the phosphodiester backbone, many are monofunctional and require a separate step to cleave the DNA or oligonucleotide backbone. − …”

“…While many DNA repair enzymes are bifunctional with the capacity to remove a base from DNA, generate an abasic site, and cleave the phosphodiester backbone, many are monofunctional and require a separate step to cleave the DNA or oligonucleotide backbone. 10 − 13 …”