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    • We also show that recruitment of MUS

    2018-11-14

    We also show that recruitment of MUS81-EME1 is required for SLX4com-mediated control of pro-inflammatory signaling. This suggests that, similar to what was previously reported for HIV biology (Laguette et al., 2014), the SLX4com likely represses LINE-1 retrotransposition through the endonucleolytic action of MUS81-EME1. Importantly, for the latter to acquire full endonuclease activity within the SLX4com, PLK1-dependent EME1 hyperphosphorylation is required, which occurs around the G2/M boundary. It would thus be interesting to investigate whether the control of endogenous retroelements mobility and the ability to repress pro-inflammatory cytokine production depend on the Protease Inhibitor Library status. Additional post-translational modifications, such as SUMOylation and PARylation, were recently shown to be required for SLX4 activity by ensuring its localization to sites of DNA damage (Gonzalez-Prieto et al., 2015; Guervilly et al., 2015; Ouyang et al., 2015). Requirement for such post-translational modifications in the recognition and processing of potential immunogenic nucleic acids remains to be investigated. Interestingly, it has been previously reported that the bone marrow of FA patients is compromised because of accumulation of DNA damage in hematopoietic stem cells (Ceccaldi et al., 2012). Our findings imply that this may also be linked to upregulated LINE-1 activity. Indeed, LINE-1 mobility is mostly repressed in cells through 5′ UTR methylation (Woodcock et al., 1997; Yu et al., 2001) and stem cells have a hypomethylated genome that allows enhanced LINE-1 activity (Wissing et al., 2012). Thus, absence of the FA pathway may also allow for pro-tumorigenic LINE-1 re-insertion events, especially in the light of the LINE-1 DNA deriving from the most active LINE-1 subfamily accumulating in the cytoplasm of SLX4-deficient cells. This raises the possibility that treatment with RT inhibitors, which inhibit the accumulation of immunogenic nucleic acids responsible for initiating pro-inflammatory cytokines production, may delay or prevent the onset of bone marrow failure in FA. In support, immunotherapy aiming at neutralizing a single pro-inflammatory cytokine (TNFα) has shown promising positive effects in patients (Mehta et al., 2012; Miehsler et al., 2010). Accordingly, we observed that treatment with TenoF weakly decreased the cell death of SLX4-deficient cells following treatment with TNFα or DNA damaging drugs. Of note, bone marrow failure is a clinical trait shared by additional familial cancer susceptibility syndromes (Parikh and Bessler, 2012) that could also be linked to deregulated endogenous RT. Finally, the key role played by chronic inflammation in the progression of cancer is highlighted by the fact that anti-inflammatory drugs when administered to patients can reduce the risk of progression to metastasis (Markowitz, 2007). One interesting finding from our work is that treatment with TenoF prevents inflammation caused by DNA-damaging agents such as those used in chemotherapy. This is of particular importance because it has been reported that treatment with chemotherapy may generate a pro-inflammatory environment that would select cells that are resistant to treatment (de Visser and Jonkers, 2009; Koti et al., 2015). Our data confirm the previous observation that certain DNA-damage inducing drugs can cause LINE-1 reactivation (Rudin and Thompson, 2001) and enforce the contribution of endogenous RT activities to inflammation. Furthermore, we observed a weak but reproducible decrease of pCHK1 levels in cells treated with RT inhibitors in the presence of DNA-damaging drugs. This is in agreement with previous reports of LINE-1 activity poising a mutagenic threat to the genome because of their ability to integrate at distant genomic locations. Thus, altogether our in vitro observations suggest that combination of chemotherapy with RT inhibitors could prevent the establishment of an inflammatory tumor microenvironment that would favor chemoresistance and decrease the risk of genomic instability. Thus, our study may open perspectives for the treatment of FA patients but also for reducing adverse effects of chemotherapy.