Abstract
Simple SummaryCancer stem cells (CSCs) are a tumor cell population maintaining tumor growth and promoting tumor relapse if not wholly eradicated during treatment. CSCs are often equipped with molecular mechanisms making them resistant to conventional anti-cancer therapies whose curative potential depends on DNA damage-induced cell death. An elevated expression of some key DNA repair proteins is one of such defense mechanisms. However, new research reveals that the role of critical DNA repair proteins is extending far beyond the DNA repair mechanisms. This review discusses the diverse biological functions of DNA repair proteins in CSC maintenance and the adaptation to replication and oxidative stress, anti-cancer immune response, epigenetic reprogramming, and intracellular signaling mechanisms. It also provides an overview of their potential therapeutic targeting.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.
Highlights
Recent discoveries for cancer therapy, such as antibody-based immunotherapy, and various predictive biomarkers, have shifted the focus from standard uniform treatment towards personalized approaches [1,2]
This study demonstrated that DNA damage-independent Ataxia telangiectasia mutated (ATM) activation in triple-negative breast cancer (TNBC) cancer stem cells (CSCs) induced an energy metabolism reprogramming by upregulation of the glycolysis-associated genes Glucose transporter type 1 (GLUT1) and Pyruvate kinase PKM2 and the TCA-related gene Pyruvate dehydrogenase PDHa through STAT5/FOXP3 signaling
BRCA1 and BRCA2 are involved in SMAD-dependent transcription by the binding of SMAD3 and co-activation of its target genes [112,114]. These results suggest that crosstalk between TGF-ß/SMAD signaling and the Fanconi anemia (FA)/breast cancer susceptibility (BRCA) pathway contributes to cell-fate decisions in hematopoietic stem cells (HSCs) and cancer cells upon genotoxic stress, determining their sensitivity towards DNA-damaging treatment
Summary
Recent discoveries for cancer therapy, such as antibody-based immunotherapy, and various predictive biomarkers, have shifted the focus from standard uniform treatment towards personalized approaches [1,2]. The cancer stem cells (CSCs) possess the ability to self-renew and exhibit an enhanced therapy resistance They can re-populate a tumor after initially successful therapy [5,6,7,8]. Some studies showed no difference in the levels of DNA damage quantified in the same way in CSCs and non-CSC populations [18,19,20] This controversy can be partially attributed to DNA repair pathways that can be activated independently on H2AX phosphorylation [21], different timepoints used for these analyses, inconsistent methods for CSC isolation or enrichment, and, in some cases, lack of CSC functional validation. Nfaactuora; l SkMilleArDce3l—ls;MPoDt-hLe1r—s Pargoagirnasmt mdedcadpeeanttha-plilgeagnicd 1h(oPmDo-Llo1g); R3E; SSTT—INRGep—resstsiomruelaetmorentof siinletenrcfienrgontrangsecnreips;tioTnGfFa-cßto—r; STMraAnsDfo3r—mMinogtghreorws athgafiancstot rd-beceatap;eWntnatp—leWgicinhgolemsso/liongteg3;raStTedIN; ΔGN—ps6t3im—upl6a3toirsooffoirnmtelrafcekroinnggNen-teesr;mTiGnaFl-ßd—omTarainn.sforming growth factor-beta; Wnt—Wingless/integrated; ∆Np63—p63 isoform lacking N-terminal domain
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