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.
Highlights
Cancer is expected to rank as the leading cause of death and the major barrier to increased life expectancy in the 21st century [1]
Because of the central role of base excision repair (BER) in the maintenance and repair of DNA damage following cancer treatment, BER enzymes have been the focus of numerous studies over the past two decades, leading to the development of several potent drugs that are in clinical use [25,38]
It is clear that dysregulation of DNA glycosylases plays a central role in numerous cancers and at different stages of the disease, favoring both the onset, and later stages such as metastasis [43,44,45]
Summary
Cancer is expected to rank as the leading cause of death and the major barrier to increased life expectancy in the 21st century [1]. This provides the tumors with an evolutionary advantage compared to normal tissues and appears to be a factor favoring metastasis [23] This explains why efficient repair of lesions generated by genotoxic therapeutic agents before they become toxic is one of the multiple mechanisms used by tumor cells to develop resistance to initially effective cytotoxic therapy [24,25,26]. A majority of these new therapies aims to inhibit the catalytic activity of DNA repair enzymes and/or trap enzyme-DNA complexes They may be used as adjuvants, either alone or in combination, to enhance the effectiveness of conventional drugs, so as to minimize resistance and negative side effects [30]. This review presents the recent developments in this area with a special focus on DNA glycosylases that initiate the BER pathway
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