Small‐molecule Inhibitors of DNA Base Excision Repair

Abstract

Cells rely on several DNA (deoxyribonucleic acid) repair pathways to maintain the integrity of their genetic information, including DNA base excision repair (BER). BER involves the removal of a DNA base, damaged in some way by a chemical modification, and then subsequent repair to reconstitute the DNA. Inhibition of the proteins and enzymes that mediate BER can result in cell death, especially in actively dividing cells. As such, many of these enzymes are targets for pharmaceutical research to combat cancer and severe inflammatory ailments. Small molecules have been identified that inhibit at least three of the principal enzymes of BER: an enzyme that participates in the signalling of DNA damage, an endonuclease involved in processing an intermediate of BER and a DNA polymerase. This article focuses on the known BER enzyme inhibitors, many of which are pharmaceutical candidates in clinical trials to treat disease.

Key concepts:

  • Several small molecules have been developed that inhibit the enzymes involved in DNA base excision repair.

  • Inhibition of DNA base excision repair can sensitize cells to DNA‐damaging treatments.

  • Inhibitors of the DNA base excision repair enzymes are being investigated as potential treatments for cancer and severe inflammation.

Keywords: DNA repair; PARP; APE1; DNA polymerase β; cancer; chemotherapy

Figure 1.

Mechanisms of DNA base excision repair. A DNA glycosylase removes a damaged base. The enzyme apurinic/apyrimidic endonuclease 1 (APE1) cleaves the abasic DNA strand. In short patch‐base excision repair (SP‐BER), DNA polymerase β (Pol β) inserts the appropriate deoxynucleotide and cleaves the deoxyribose phosphate (dRP) group before DNA ligase III (Lig III) and X‐ray cross‐complimenting protein 1 (XRCC1) resolve the structure. Poly(ADP‐ribose) polymerase (PARP1) also participates in this process. In long patch‐base excision repair (LP‐BER), DNA synthesis is carried out by a complex of several proteins, including DNA polymerases δ and ɛ (Pol δ/ɛ), replication factor C (RFC) and proliferating cellular nuclear antigen (PCNA). Flap endonuclease 1 (FEN‐1) cleaves the displaced DNA strand, whereas DNA ligase I (Lig I) seals the DNA nick.

Figure 2.

The role of PARP in the cellular response to DNA damage. The enzyme poly(ADP‐ribose) polymerase (PARP) recognizes DNA damage caused by exogenous molecules and oxidative stress and signals for DNA repair. If the DNA damage is limited, PARP participates in the DNA repair process and allows cells to survive the insult. In cases of severe damage, PARP may become very hyperstimulated. Given that PARP uses the electron carrier molecule NAD+ as a substrate, a cell with overactive PARP will deplete its reserves of NAD+, and therefore ATP, which can lead to necrotic cell death. In either case, a small‐molecule inhibitor of PARP can lead to an apoptotic cell death by shutting down DNA metabolism (but not glycolytic metabolism).

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Further Reading

Lord CJ and Ashworth A (2008) Targeted therapy for cancer using PARP inhibitors. Current Opinion in Pharmacology 8(4): 363–369.

Nouspikel T (2009) DNA repair in mammalian cells. Cellular and Molecular Life Sciences 66(6): 994–1009.

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Reed AM, Fishel ML and Kelly MR (2009) Small‐molecule inhibitors of proteins involved in base excision repair potentiate the anti‐tumorigenic effect of existing chemotherapeutics and irradiation. Future Oncology 5(5): 713–226.

Sánchez‐Pérez I (2006) DNA repair inhibitors in cancer treatment. Clinical and Translational Oncology 8(9): 642–646.

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Praggastis, V Alexandra, and Rice, Kevin P(Mar 2010) Small‐molecule Inhibitors of DNA Base Excision Repair. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022212]