Cytoskeleton
Microtubule polyglutamylation is thought to contribute to cytoskeletal organization, but little is known about its functional relevance. Lacroix et al. overexpressed tubulin Tyr ligase-like proteins (TTLLs), which catalyse the addition of glutamylated chains of different lengths, in interphase HeLa cells (which normally have low levels of glutamylation). Long Glu side chains induced microtubule loss more efficiently than short ones. Microtubule disassembly requires the activity of spastin (a microtubule-severing protein), which is directly activated by polyglutamylation. The authors confirmed spastin-mediated severing of differentially modified microtubules in vitro and showed that TTLLs which generate long Glu chains also activate the microtubule-severing protein katanin p60 in vivo. So, polyglutamylation might control microtubule dynamics, but how it is spatiotemporally regulated remains to be determined.
Autophagy
During autophagy, double-membrane autophagosomes sequester cellular components and fuse with lysosomes to form autolysosomes, which degrade their contents and regenerate nutrients. Autophagy is induced by starvation, but its regulation and the autolysosome fate are unclear. Yu et al. observed that shortly after starvation initiation, lysosomes disappear by forming autolysosomes, but reform and reach their initial numbers after 12 hours of starvation. Microscopy analysis revealed that the regenerated lysosomes originate from tubules and vesicles deriving from autolysosomes. Which signals control this process? Mammalian target of rapamycin (mTOR) is a nutrient-responsive kinase, the inactivation of which on starvation induces autophagy. Nutrients generated by autophagy were shown to stimulate mTOR signalling, which downregulates autophagy and triggers lysosome formation. Thus, mTOR signals to stop autophagy and restore lysosome homeostasis.
DNA repair
The Fanconi anaemia pathway regulates the removal of interstrand DNA cross links. It uses a nuclear protein complex that ubiquitylates the downstream effector FANCD2, among others, leading to the formation of DNA repair structures. Fanconi anaemia proteins resolve DNA double-strand breaks (DSBs) created at cross links, but how this occurs was unclear. FANCC-deficient cells are sensitive to DNA cross links, and Pace et al. now find that the concomitant disruption of Ku70 (also known as XRCC6) increases resistance to cross-linkers; this indicates a genetic interaction between FANCC and Ku70. Ku70 is known to bind DSB ends, thereby committing them to abortive non-homologous end joining repair, which interferes with homologous recombination. The authors show that the Fanconi anaemia pathway antagonizes Ku70 activity and diverts repair towards homologous recombination, possibly through the 3′–5′ exonuclease activity of FANCD2.
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In brief. Nat Rev Mol Cell Biol 11, 465 (2010). https://doi.org/10.1038/nrm2935
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DOI: https://doi.org/10.1038/nrm2935