Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice

Reproductive parameters of tropical lesser noddies respond to local variations in oceanographic conditions and weather

Most attempts to link seabirds and climate/oceanographic effects have concerned the Atlantic and Pacific Oceans with comparatively few studies in the tropical Indian Ocean. This paper examines the reproductive response of the lesser noddy Anous tenuirostris to temporal fluctuations in oceanographic and climatic conditions using 8 years of monitoring data from Aride Island (Seychelles), tropical Western Indian Ocean. We tested the hypothesis that breeding parameters (mean hatching date, mean egg size, hatching and fledging successes) and chick growth are influenced by local, seasonal oceanographic conditions as expressed by ocean primary productivity (surface chlorophyll-a concentrations; CC), sea surface temperature (SST) and wind speed. We also examined the relationship between lesser noddy breeding parameters and climate conditions recorded at the basin-wide scale of the Indian Ocean (Indian Ocean Dipole Mode Index, DMI). Our findings suggest that birds had a tendency to lay slightly larger eggs during breeding seasons (years) with higher CC during AprileJune (pre-laying, laying and incubation periods). Hatching date was positively related to SST in AprileJune, with the regression parameters suggesting that each 0.5 C increase in SST meant a delay of approx.10 days in hatching date. A negative linear relationship was also apparent between hatching success and SST in JuneeAugust (hatching and chick-rearing periods), while the quadratic regression models detected a significant effect of wind speed in JuneeAugust on fledging success. Body mass increments of growing chicks averaged over 7-day periods were positively related with (2-week) lagged CC values and negatively related with (2-week) lagged SST values. No significant relationship between DMI and lesser noddy breeding parameters was found, but DMI indices were strongly correlated with local SST. Altogether, our results indicate that the reproduction of this top marine predator is dictated by fluctuations in local environmental conditions around the colony, while the effects of large-scale oceanographic processes (DMI) on our study population might be mediated by an effect on local SST.DM and TC were supported by post-doctoral grants SFRH/BPD/ 66672/2009 and SFRH/BPD/46967/2008, respectively