Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation<jats:sup>1</jats:sup>, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers<jats:sup>2</jats:sup>. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K—a group of naphthoquinones that includes menaquinone and phylloquinone<jats:sup>3</jats:sup>—confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-4<jats:sup>4,5</jats:sup>, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle<jats:sup>6</jats:sup>. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Although p53 inactivation promotes genomic instability<jats:sup>1</jats:sup> and presents a route to malignancy for more than half of all human cancers<jats:sup>2,3</jats:sup>, the patterns through which heterogenous <jats:italic>TP53</jats:italic> (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases—<jats:italic>Trp53</jats:italic> (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications—each associated with specific histological stages across the premalignant and malignant spectrum. Despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations. Thus, loss of p53—the ‘guardian of the genome’—is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of <jats:italic>TP53-</jats:italic>mutant tumours.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes<jats:sup>1–4</jats:sup>. Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide<jats:sup>4–13</jats:sup>, but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)–STING filament complex from a <jats:italic>Sphingobacterium faecium</jats:italic> cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR–STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals<jats:sup>5</jats:sup>. The active bacterial TIR–STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD<jats:sup>+</jats:sup> hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Telomeres, the natural ends of linear chromosomes, comprise repeat-sequence DNA and associated proteins<jats:sup>1</jats:sup>. Replication of telomeres allows continued proliferation of human stem cells and immortality of cancer cells<jats:sup>2</jats:sup>. This replication requires telomerase<jats:sup>3</jats:sup> extension of the single-stranded DNA (ssDNA) of the telomeric G-strand ((TTAGGG)<jats:sub><jats:italic>n</jats:italic></jats:sub>); the synthesis of the complementary C-strand ((CCCTAA)<jats:sub><jats:italic>n</jats:italic></jats:sub>) is much less well characterized. The CST (CTC1–STN1–TEN1) protein complex, a DNA polymerase α-primase accessory factor<jats:sup>4,5</jats:sup>, is known to be required for telomere replication in vivo<jats:sup>6–9</jats:sup>, and the molecular analysis presented here reveals key features of its mechanism. We find that human CST uses its ssDNA-binding activity to specify the origins for telomeric C-strand synthesis by bound Polα-primase. CST-organized DNA polymerization can copy a telomeric DNA template that folds into G-quadruplex structures, but the challenges presented by this template probably contribute to telomere replication problems observed in vivo. Combining telomerase, a short telomeric ssDNA primer and CST–Polα–primase gives complete telomeric DNA replication, resulting in the same sort of ssDNA 3′ overhang found naturally on human telomeres. We conclude that the CST complex not only terminates telomerase extension<jats:sup>10,11</jats:sup> and recruits Polα–primase to telomeric ssDNA<jats:sup>4,12,13</jats:sup> but also orchestrates C-strand synthesis. Because replication of the telomere has features distinct from replication of the rest of the genome, targeting telomere-replication components including CST holds promise for cancer therapeutics.</jats:p>