| Резюме: | <p>Homologous recombination (HR) is a key DNA repair pathway essential for cell viability. Counter-intuitively, HR deficiency can trigger carcinogenesis. Understanding the mechanisms that allow the rampant proliferation of HR-deficient tumour cells is crucial for the development of improved therapeutic modalities to selectively inhibit the outgrowth of these cells.</p> <p>Recently, we identified extracellular signal-regulated kinase 1 (ERK1) as a factor required for the proliferation of BRCA2-deficient cells regardless of their p53 status (Carlos <em>et al</em>., 2013). Here, we report the therapeutic potential of two chemical ERK1/2 inhibitors, SCH772984 and VTX-11e, for selective targeting of HR-deficient tumours due to their ability to specifically obstruct proliferation of HR-deficient cells.</p> <p>G-quadruplexes (G4s), secondary DNA structures formed by guanine-rich (G-rich) single-stranded DNA (ssDNA), represent natural barriers to replication fork progression. In this study, we demonstrate that treatment with G4 stabilisers selectively decreases viability of BRCA2- and RAD51-deficient cells. We identify DNA damage response activation and acute replication stress as main sources for the cellular toxicity of G4 stabilisers specifically in the context of HR deficiency.</p> <p>Taken together, the results presented here indicate that HR is required for replication of genomic regions with G4-forming potential to prevent genomic instability stemming from inefficient replication of these sites. Persistent G4 structures lead to DNA damage accumulation, which enables selective killing of cells whose HR-mediated repair has been compromised. This is an important finding with profound implications for the therapeutic exploitation of HR deficiency in the clinic.</p>
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