DNA Repair Pathways in Cancer Therapy and Resistance

Abstract

DNA repair pathways are triggered to maintain genetic stability and integrity when mammalian cells are exposed to endogenous or exogenous DNA-damaging agents. The deregulation of DNA repair pathways is associated with the initiation and progression of cancer. As the primary anti-cancer therapies, ionizing radiation and chemotherapeutic agents induce cell death by directly or indirectly causing DNA damage, dysregulation of the DNA damage response may contribute to hypersensitivity or resistance of cancer cells to genotoxic agents and targeting DNA repair pathway can increase the tumor sensitivity to cancer therapies. Therefore, targeting DNA repair pathways may be a potential therapeutic approach for cancer treatment. A better understanding of the biology and the regulatory mechanisms of DNA repair pathways has the potential to facilitate the development of inhibitors of nuclear and mitochondria DNA repair pathways for enhancing anticancer effect of DNA damage-based therapy.

Keywords: DNA damage; DNA repair pathways; cancer therapy; drug resistance; mitochondrial DNA.

FIGURE 1

DNA damage response. DNA damage is caused by endogenous agent oxygen species (ROS) or exogenous agents such as UV light, ionizing radiation (IR) and chemotherapy agents. DNA damage response (DDR) is induced to deal with the lesions, including signal transduction, transcriptional regulation, cell-cycle checkpoints, induction of apoptosis, multiple DNA repair pathways as well as damage tolerance processes. DNA repair pathways include nuclear and mitochondrial DNA repair pathways. Direct repair, BER, MMR and recombinational repair (HR and NHEJ) are existence in both nuclear and mitochondrial repair systems. NER has been reported only appearance in nucleus, and the existence of TLS pathway in mitochondria is unknown. NDNA, nuclear DNA; MtDNA, mitochondrial DNA; BER, base excision repair; HR, homologous recombination repair; NHEJ, non-homologous end joining; MMR, mismatch repair; TLS, translesion synthesis; NER, nucleotide excision repair.

FIGURE 2

Mechanism and function of PARP and PARP inhibitors. The catalytic function of PARP1 is activated through binding to the SSBs site cuased by alkylating agents. Activated PARP1 undergo PARylation and recruitment of a serials of key DNA repair effectors involved in BER to repair DNA lesion. Finally, PARP1 release from DNA and regain inactive state. PARP inhibitors binds the catalytic site of PARP and impaired of the enzymatic activity of PARP which “trap” PARP1 on DNA, results in suppression of the catalytic cycle of PARP1 and BER. Trapping PARP1 on DNA lesion also collapses DNA replication fork, therefore transforming SSBs into genotoxic DSBs. This type of DNA lesion would normally induce HR for repairing damaged DNA. However, if HR-defective exist in tumor cells, including BRCA1/2 deficiency or mutation, another less effective and error-prone DSBs repair pathway NHEJ or alt-NHEJ could be utilized, which causing genomic instability, chromosomal fusions/translocations and subsequently inducing cell death. SSBs, single-strand breaks; DSB, double-strand break; BER, base excision repair; alt-NHEJ, alternative nonhomologous end joining; NHEJ, non-homologous end joining; HR, homologous recombination repair.