Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>Aggressive and metastatic cancers show enhanced metabolic plasticity<jats:sup>1</jats:sup>, but the precise underlying mechanisms of this remain unclear. Here we show how two NOP2/Sun RNA methyltransferase 3 (NSUN3)-dependent RNA modifications—5-methylcytosine (m<jats:sup>5</jats:sup>C) and its derivative 5-formylcytosine (f<jats:sup>5</jats:sup>C) (refs.<jats:sup>2–4</jats:sup>)—drive the translation of mitochondrial mRNA to power metastasis. Translation of mitochondrially encoded subunits of the oxidative phosphorylation complex depends on the formation of m<jats:sup>5</jats:sup>C at position 34 in mitochondrial tRNA<jats:sup>Met</jats:sup>. m<jats:sup>5</jats:sup>C-deficient human oral cancer cells exhibit increased levels of glycolysis and changes in their mitochondrial function that do not affect cell viability or primary tumour growth in vivo; however, metabolic plasticity is severely impaired as mitochondrial m<jats:sup>5</jats:sup>C-deficient tumours do not metastasize efficiently. We discovered that CD36-dependent non-dividing, metastasis-initiating tumour cells require mitochondrial m<jats:sup>5</jats:sup>C to activate invasion and dissemination. Moreover, a mitochondria-driven gene signature in patients with head and neck cancer is predictive for metastasis and disease progression. Finally, we confirm that this metabolic switch that allows the metastasis of tumour cells can be pharmacologically targeted through the inhibition of mitochondrial mRNA translation in vivo. Together, our results reveal that site-specific mitochondrial RNA modifications could be therapeutic targets to combat metastasis.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Chromosome segregation errors during cell divisions generate aneuploidies and micronuclei, which can undergo extensive chromosomal rearrangements such as chromothripsis<jats:sup>1–5</jats:sup>. Selective pressures then shape distinct aneuploidy and rearrangement patterns—for example, in cancer<jats:sup>6,7</jats:sup>—but it is unknown whether initial biases in segregation errors and micronucleation exist for particular chromosomes. Using single-cell DNA sequencing<jats:sup>8</jats:sup> after an error-prone mitosis in untransformed, diploid cell lines and organoids, we show that chromosomes have different segregation error frequencies that result in non-random aneuploidy landscapes. Isolation and sequencing of single micronuclei from these cells showed that mis-segregating chromosomes frequently also preferentially become entrapped in micronuclei. A similar bias was found in naturally occurring micronuclei of two cancer cell lines. We find that segregation error frequencies of individual chromosomes correlate with their location in the interphase nucleus, and show that this is highest for peripheral chromosomes behind spindle poles. Randomization of chromosome positions, Cas9-mediated live tracking and forced repositioning of individual chromosomes showed that a greater distance from the nuclear centre directly increases the propensity to mis-segregate. Accordingly, chromothripsis in cancer genomes<jats:sup>9</jats:sup> and aneuploidies in early development<jats:sup>10</jats:sup> occur more frequently for larger chromosomes, which are preferentially located near the nuclear periphery. Our findings reveal a direct link between nuclear chromosome positions, segregation error frequencies and micronucleus content, with implications for our understanding of tumour genome evolution and the origins of specific aneuploidies during development.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Strychnine is a natural product that, through isolation, structural elucidation and synthetic efforts, shaped the field of organic chemistry. Currently, strychnine is used as a pesticide to control rodents<jats:sup>1</jats:sup> because of its potent neurotoxicity<jats:sup>2,3</jats:sup>. The polycyclic architecture of strychnine has inspired chemists to develop new synthetic transformations and strategies to access this molecular scaffold<jats:sup>4</jats:sup>, yet it is still unknown how plants create this complex structure. Here we report the biosynthetic pathway of strychnine, along with the related molecules brucine and diaboline. Moreover, we successfully recapitulate strychnine, brucine and diaboline biosynthesis in <jats:italic>Nicotiana benthamiana</jats:italic> from an upstream intermediate, thus demonstrating that this complex, pharmacologically active class of compounds can now be harnessed through metabolic engineering approaches.</jats:p>