Altering DNA Repair to Improve Radiation Therapy: Specific and Multiple Pathway Targeting

Abstract

Radiation therapy (RT) is widely used in cancer care strategies. Its effectiveness relies mainly on its ability to cause lethal damage to the DNA of cancer cells. However, some cancers have shown to be particularly radioresistant partly because of efficient and redundant DNA repair capacities. Therefore, RT efficacy might be enhanced by using drugs that can disrupt cancer cells' DNA repair machinery. Here we review the recent advances in the development of novel inhibitors of DNA repair pathways in combination with RT. A large number of these compounds are the subject of preclinical/clinical studies and target key enzymes involved in one or more DNA repair pathways. A totally different strategy consists of mimicking DNA double-strand breaks via small interfering DNA (siDNA) to bait the whole DNA repair machinery, leading to its global inhibition.

Keywords: DNA damage; inhibition; radioresistance; radiotherapy; repair systems.

Figure 1

DNA damage repair after radiation therapy. In irradiated cells, a number of DNA lesions are induced including single (SSB) and double-strand breaks (DSB). (A) SSBs are corrected by the part of base excision repair (BER) known as single-strand break repair (SSBR). The binding of PARP to SSB activates its auto-PARylation and leads to the recruitment of BER/SSBR proteins including AP endonucleases (APE1), XRCC1 (helper protein), PCNA, FEN, PNK, and DNA polymerases (Pol; damage processing) and DNA ligases. (B) In c-NHEJ, DSB is recognized by the Ku80-Ku70 heterodimer, which leads to DNA-dependent protein kinase catalytic subunit DNA-PKcs recruitment, gathering the DNA-PK complex and activating its kinase activity. This leads to the involvement of repair proteins (XRCC4, DNA ligase IV and others), which perform the processing and final junction reaction. (C) When c-NHEJ is impaired, an alternative pathway called a-EJ (alternative EJ) takes place and involves mainly PARP1, XRCC1, ligase III, MRN complex and the DNA polymerase θ. (D) In HR, after ATM activation, the DSB site is bounded by the MRE11-RAD50-NBS1 complex (MRN). The consequence is the phosphorylation of a set of targets including H2AX (γ-H2AX), localized at the site of DSB. HR uses the sister chromatid as a model to repair DSB. First, the resection of the DNA at DSB results in a 3′ single-strand DNA, which is then coated by proteins of replication A (RPA). Subsequently, proteins of the RAD family are recruited and mediate the invasion of the homologous strand of the sister chromatid, leading to the formation of Holliday junctions. DNA polymerases can then synthetize across the missing regions. The Holliday junctions are finally resolved by cleavage and followed by ligation of adjacent ends. Represents inhibitors of DNA repair in preclinical or clinical development.