PerspectiveDNA Repair

Drugging DNA repair

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Science  03 Jun 2016:
Vol. 352, Issue 6290, pp. 1178-1179
DOI: 10.1126/science.aab0958

All the cells in our bodies suffer many thousands of DNA lesions every day (1). The vast majority of these lesions are safely dealt with by cellular DNA repair and associated DNA damage response (DDR) activities that are, as a consequence, vital for life. Defects in or deregulation of our DNA repair/DDR systems are linked to many human pathologies (2). Yet, perhaps counterintuitively, pharmacological inhibitors of DNA repair/DDR have considerable potential in treating various human diseases, particularly cancer.

Many human proteins function in or affect DNA repair/DDR. These include factors that sense various types of damaged DNA, those that mediate the enzymatic stages of DNA repair, and yet others that control interactions between various DNA repair/DDR components and modulate other cellular processes such as DNA replication, transcription, control of chromatin structure, and apoptosis. Because many DNA repair/DDR proteins are enzymes, it has proven possible to develop druglike compounds that selectively modulate their activity and, therefore, to explore these DNA repair/DDR proteins as potential therapeutic targets.

DNA damage and defective DNA repair can cause cancer through the accrual of mutations in genomic DNA. Many cancers are also particularly susceptible to DNA damage, and this is exploited by radiotherapy and chemotherapy treatments. Tumor cells' susceptibilities to such treatments may be explained by their high underlying levels of DNA damage—for example, caused by oncogene-induced replication stress, shortened telomeres, or DNA repair/DDR defects (2). Because cancer cells suffering from replication stress depend more on DNA repair/DDR than do normal cells for survival, inhibitors of the DDR kinases ataxia telangiectasia mutated (ATM) and Rad3-related (ATR) and checkpoint kinase 1 (CHK1) or the cell-cycle–related kinase WEE1 are currently being tested in the clinic for their ability to selectively kill tumor cells (3) (see the figure, left).

DNA repair/DDR inhibitors in cancer treatment.

(Left) Deregulated cellular metabolism can result in cancer cells having high DNA damage loads (red dots), making them particularly dependent on DNA repair/DDR for survival. (Middle) DNA repair/DDR inhibitors can be used to potentiate radio- (IR, ionizing radiation) or chemotherapy. (Right) Mutations (yellow dots on orange chromosomes) can make cancer cells more susceptible to DNA repair/DDR inhibitors—the synthetic-lethal paradigm for selectively killing cancer cells with particular mutations.


Cancer cells also often exhibit abnormal redox homeostasis, resulting in high levels of oxidative stress that cause damage to DNA or its nucleotide precursors. Enzymes such as MutT homolog 1 (MTH1) (4, 5) are involved in preventing oxidized nucleotides from becoming incorporated into, and therefore damaging, DNA. Targeting such enzymes or exploiting other aspects of altered nucleotide metabolism in cancer cells (6) thus offers ways to selectively introduce toxic DNA damage into cancer cells. DNA repair/DDR inhibitors are also being explored in combination with widely used radio- and chemotherapy regimens (see the figure, middle).

Another strategy for the therapeutic targeting of DNA repair/DDR has been to exploit the cancer-specific loss of tumor suppressors, such as P53, breast cancer 1 and 2 (BRCA1/2), or ATM, that control or are otherwise linked to DNA repair/DDR. In some cases, these losses lead to cancer cells becoming much more reliant than normal cells on the DNA repair/DDR pathways that they still possess. This reliance can manifest itself as a total dependency on a particular pathway that is otherwise nonessential in normal cells. This phenomenon is termed synthetic lethality. It has been leveraged as a pharmacological strategy by the demonstration that cancer cells with hereditary or somatically acquired mutations in BRCA1 or BRCA2, resulting in defective DNA repair by homologous recombination, are hypersensitive to inhibition of the DNA-repair enzyme poly(ADP-ribose) polymerase (PARP) (7, 8) (see the figure, right). Thus, the PARP inhibitor olaparib has become the first DNA repair enzyme inhibitor marketed as a drug, gaining regulatory approval in 2014 for treating BRCA-mutated ovarian cancers. In a recent trial, 33% of patients with metastatic castration-resistant prostate cancers responded to olaparib (9). It seems likely that PARP inhibitors will be approved for other neoplasms, either as stand-alone agents or combined with other therapies. Given the success of the BRCA-PARP paradigm, further synthetic-lethal cancer therapies are actively being pursued.

In certain instances, human disease appears to arise through DNA repair/DDR pathway hyperactivation, so drugs that dampen down these pathways could be used in disease suppression (2). For instance, PARP hyperactivity has been linked to ischemia-reperfusion injury, inflammatory diseases, and some cardiovascular diseases, with studies in model organisms suggesting how PARP inhibition might lead to disease suppression (10). Furthermore, as viruses and microbial infectious agents use their own or host-cell DNA repair/DDR mechanisms, specific inhibition of such mechanisms might offer protection from infections (11). Pathologies associated with certain genetic diseases, such as Huntington's disease, are caused by the expansion of DNA-repeat sequences in both germline and somatic tissues. Drugs that inhibit the DNA repair enzyme OGG1 or other factors involved in such expansions therefore have the potential to slow disease progression, as do inhibitors of the DDR protein ATM, whose activity has been linked to Huntington's disease pathologies (12, 13).

Although individuals can reduce their load of DNA lesions through changes in diet or environmental exposures, it is clear that DNAdamage induction is an inevitable outcome of the biochemical processes that sustain life (1). However, strategies to lower DNA damage loads by bolstering DNA repair/DDR processes could reduce the incidence or severity of cancer and other age-related diseases. Bolstering DNA repair/DDR could be accomplished by gene therapy, pharmacological activators of DNA repair/DDR components, or by developing drugs to trigger homeostatic mechanisms that up-regulate the expression or activity of these components. Such “compensation” strategies could be particularly efficacious in individuals with genetic diseases such as Hutchinson-Gilford progeria, whose cells experience abnormally high DNA damage levels (14), or diseases where hyperactivated DDR pathways mediate pathogenesis.

Therapeutically exploiting DNA repair is still in its infancy, and DNA repair/DDR mechanisms are under intense investigation. With the growing realization that these mechanisms affect many areas of human health and disease, it seems likely that we will soon witness the development of important new DNA repair/DDR inhibitors for the treatment of various human diseases.

References and Notes

  1. Acknowledgments: S.P.J. founded and scientifically led KuDOS Pharmaceuticals, which developed the drug Lynparza (olaparib). T.H. is named inventor on patents for the use of PARP and MTH1 inhibitors in treatments of cancer.
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