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Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel−/− cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that Eµ-Myc/cRel−/− lymphomas highly resemble wild-type (WT) Eµ-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i) CCT244747. Further analysis demonstrated that this is a consequence of Eµ-Myc/cRel−/− lymphomas having lost expression of CHK1 protein itself, an effect that also results in resistance to CCT244747 treatment in vivo. Similar down-regulation of CHK1 protein levels was also seen in CHK1i resistant U2OS osteosarcoma and Huh7 hepatocellular carcinoma cells. Further investigation revealed that the deubiquitinase USP1 regulates CHK1 proteolytic degradation and that its down-regulation in our model systems is responsible, at least in part, for these effects. We demonstrate that treating WT Eµ-Myc lymphoma cells with the USP1 inhibitor ML323 was highly effective at reducing tumour burden in vivo. Targeting USP1 activity may thus be an alternative therapeutic strategy in MYC-driven tumours.

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Process-based, mechanistic investigations of organic matter transformation and diagenesis directly beneath the sediment–water interface (SWI) in Arctic continental shelves are vital as these regions are at greatest risk of future change. This is in part due to disruptions in benthic–pelagic coupling associated with ocean current change and sea ice retreat. Here, we focus on a high-resolution, multi-disciplinary set of measurements that illustrate how microbial processes involved in the degradation of organic matter are directly coupled with inorganic and organic geochemical sediment properties (measured and modelled) as well as the extent/depth of bioturbation. We find direct links between aerobic processes, reactive organic carbon and highest abundances of bacteria and archaea in the uppermost layer (0–4.5 cm depth) followed by dominance of microbes involved in nitrate/nitrite and iron/manganese reduction across the oxic-anoxic redox boundary (approx. 4.5–10.5 cm depth). Sulfate reducers dominate in the deeper (approx. 10.5–33 cm) anoxic sediments which is consistent with the modelled reactive transport framework. Importantly, organic matter reactivity as tracked by organic geochemical parameters ( n -alkanes, n -alkanoic acids, n -alkanols and sterols) changes most dramatically at and directly below the SWI together with sedimentology and biological activity but remained relatively unchanged across deeper changes in sedimentology. This article is part of the theme issue ‘The changing Arctic Ocean: consequences for biological communities, biogeochemical processes and ecosystem functioning’.

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