Beyond the Double-Strand Breaks: The Role of DNA Repair Proteins in Cancer Stem-Cell Regulation

Abstract

Cancer stem cells (CSCs) are pluripotent and highly tumorigenic cells that can re-populate a tumor and cause relapses even after initially successful therapy. As with tissue stem cells, CSCs possess enhanced DNA repair mechanisms. An active DNA damage response alleviates the increased oxidative and replicative stress and leads to therapy resistance. On the other hand, mutations in DNA repair genes cause genomic instability, therefore driving tumor evolution and developing highly aggressive CSC phenotypes. However, the role of DNA repair proteins in CSCs extends beyond the level of DNA damage. In recent years, more and more studies have reported the unexpected role of DNA repair proteins in the regulation of transcription, CSC signaling pathways, intracellular levels of reactive oxygen species (ROS), and epithelial–mesenchymal transition (EMT). Moreover, DNA damage signaling plays an essential role in the immune response towards tumor cells. Due to its high importance for the CSC phenotype and treatment resistance, the DNA damage response is a promising target for individualized therapies. Furthermore, understanding the dependence of CSC on DNA repair pathways can be therapeutically exploited to induce synthetic lethality and sensitize CSCs to anti-cancer therapies. This review discusses the different roles of DNA repair proteins in CSC maintenance and their potential as therapeutic targets.

JAG1 Intracellular Domain Enhances AR Expression and Signaling and Promotes Stem-like Properties in Prostate Cancer Cells

“…CSCs can undergo extensive metabolic reprogramming [ 47 ], showing rapid DNA damage repair [ 48 ] and enhanced cancer drug resistance [ 49 ]. DNA repair proteins play crucial roles in CSC maintenance and adaptation to replication and oxidative stress [ 50 ]. Among them, testis-expressed protein 264 (TEX264) [ 51 ] and forkhead box M1 (FOXM1) [ 52 ] are involved in DNA repair response.…”

Validation of CD98hc as a Therapeutic Target for a Combination of Radiation and Immunotherapies in Head and Neck Squamous Cell Carcinoma

“…These molecules are detected by immune cells, resulting in the activation of the adaptive immune system and the release of pro-inflammatory cytokines and chemokines [ 35 , 36 ]. Additionally, several reports have shown that radiation-induced accumulation of cytosolic DNA triggers activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS/STING) pathway, one of the critical mechanisms activating antitumor immune response [ 37 , 38 , 39 , 40 , 41 ]. The immunomodulatory effects of radiotherapy open up an avenue for radioimmunotherapy combination treatment.…”

A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

“…With high plasticity from a dormant status to highly proliferative, depending on the tumor microenvironment, [6,7], activation of DNA repair systems [8][9][10], and modulation of autophagic and apoptotic cell death [11][12][13], CSC are referred to as the source of chemoresistance. However, the exact mechanism of resistance is not clear and understanding mechanisms underlying drug resistance and identifying novel modalities of therapy has remained as the major focus of research in the field [14].…”

“…Chemoresistance in glioma cells is a complex process that involves multiple factors including dysregulation of programmed cell death pathways [3], presence of tumor residues that contain cancer stem cell (CSC) populations [4, 5], and the activation of DNA repair system. With high plasticity from a dormant status to highly proliferative, depending on the tumor microenvironment, [6, 7], activation of DNA repair systems [8–10], and modulation of autophagic and apoptotic cell death [11–13], CSC are referred to as the source of chemoresistance. However, the exact mechanism of resistance is not clear and understanding mechanisms underlying drug resistance and identifying novel modalities of therapy has remained as the major focus of research in the field [14].…”