The association of proteins with metals, metalation, is challenging because the tightest binding metals are rarely the correct ones. Inside cells, correct metalation is enabled by controlled bioavaila Show more
The association of proteins with metals, metalation, is challenging because the tightest binding metals are rarely the correct ones. Inside cells, correct metalation is enabled by controlled bioavailability plus extra mechanisms for tricky combinations such as iron and manganese. Show less
Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemothera Show more
Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8 + T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity. Show less
Iron-sulfur (Fe/S) clusters are structurally and functionally diverse cofactors that are found in all domains of life. (57)Fe Mössbauer spectroscopy is a technique that provides information about the Show more
Iron-sulfur (Fe/S) clusters are structurally and functionally diverse cofactors that are found in all domains of life. (57)Fe Mössbauer spectroscopy is a technique that provides information about the chemical nature of all chemically distinct Fe species contained in a sample, such as Fe oxidation and spin state, nuclearity of a cluster with more than one metal ion, electron spin ground state of the cluster, and delocalization properties in mixed-valent clusters. Moreover, the technique allows for quantitation of all Fe species, when it is used in conjunction with electron paramagnetic resonance (EPR) spectroscopy and analytical methods. (57)Fe-Mössbauer spectroscopy played a pivotal role in unraveling the electronic structures of the "well-established" [2Fe-2S](2+/+), [3Fe-4S](1+/0), and [4Fe-4S](3+/2+/1+/0) clusters and -more-recently- was used to characterize novel Fe/S clustsers, including the [4Fe-3S] cluster of the O2-tolerant hydrogenase from Aquifex aeolicus and the 3Fe-cluster intermediate observed during the reaction of lipoyl synthase, a member of the radical SAM enzyme superfamily. Show less