DNA Double Strand Break Repair - Related Synthetic Lethality

Abstract

Cancer is a heterogeneous disease with a high degree of diversity between and within tumors. Our limited knowledge of their biology results in ineffective treatment. However, personalized approach may represent a milestone in the field of anticancer therapy. It can increase specificity of treatment against tumor initiating cancer stem cells (CSCs) and cancer progenitor cells (CPCs) with minimal effect on normal cells and tissues. Cancerous cells carry multiple genetic and epigenetic aberrations which may disrupt pathways essential for cell survival. Discovery of synthetic lethality has led a new hope of creating effective, personalized anti-tumor treatment. Synthetic lethality occurs when simultaneous inactivation of two genes or their products causes cell death whereas individual inactivation of either gene is not lethal. The effectiveness of numerous anti-tumor therapies depend on induction of DNA damage therefore tumor cells expressing abnormalities in genes whose products are crucial for DNA repair pathways are promising targets for synthetic lethality. Here, we discuss mechanistic aspects of synthetic lethality in the context of deficiencies in DNA double strand break repair pathways. In addition, we review clinical trials utilizing synthetic lethality interactions and discuss the mechanisms of resistance.

RAD52 as a Potential Target for Synthetic Lethality-Based Anticancer Therapies

“…While normal cells treated with PARPi are able to efficiently repair DSBs using BRCA1/2-mediated HR, cancer cells carrying defects in HR accumulate high levels of toxic lesions that leads to synthetic lethality and apoptosis [7]. Recently, three other PARPi: rucaparib, niraparib, and talazoparib, obtained FDA approval, and numerous compounds are in various stages of clinical trials as single-agent therapies and in combination with other cytotoxic compounds or radiotherapy [8].…”

Eradication of LIG4-deficient glioblastoma cells by the combination of PARP inhibitor and alkylating agent

“…Due to the growing knowledge of genetic and epigenetic changes in tumors the concept of synthetic lethality became lately one of the main areas of searching for new therapy candidates. The phenomenon occurs when simultaneous loss of two genes causes cell death whereas loss of each of these genes individually is not lethal [11]. For instance, BRCA1/2 deficient tumors with impaired homologous recombination repair were reported to be sensitive to PARP inhibition [16–17].…”

“…Two mechanisms predominantly responsible for repair of DSBs in proliferating cells are BRCA1/2-mediated homologous recombination (HR) and DNA-PK-mediated non-homologous end-joining (D-NHEJ). When proper functioning of one of these pathways is compromised, cells redirect functions to an alternative mechanism – PARP1-dependant backup NHEJ (B-NHEJ) [9–11]. PARP1 is a protein playing a critical role in other processes decreasing the number of lethal DSBs - by activation of base excision repair (BER), single strand break (SSB) repair or HR activation at stalled replication forks [12–13].…”

Experimental evolution of extremophile levels of radiation resistance in Escherichia coli

“…Gamma radiation works primarily via H2O radiolysis to produce reactive oxygen species (ROS) (1, 2). Direct ionization and indirect oxidation of DNA through ROS leads to the accumulation of double-strand breaks (DSBs) of genomic DNA, which are lethal if left unrepaired (3)(4)(5)(6)(7). Cellular proteomes and lipidomes are also damaged (8)(9)(10)(11)(12)(13)(14)(15)(16).…”