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Through CRISPR–Cas9 screen, Dev et al. identified that SHLD1/2 inhibition contributes to PARP-inhibitor resistance. Mechanistically, SHLDs promote non-homologous end-joining and antagonize homologous recombination.
Using a heterokaryon system, Mai et al. demonstrate that NKX3-1 is downstream of IL-6–STAT3, regulates endogenous OCT4 expression during human iPSC reprogramming, and can also substitute for exogenous OCT4 in the reprogramming cocktail.
Urra et al. discover that IRE1α, an ER stress mediator, interacts with
filamin A and controls actin dynamics and cell migration in mouse, Drosophila and zebrafish models in a manner independent
of its canonical function.
Using electron and three-dimensional structured illumination microscopy methods, Jana et al. characterize the ciliary base in four different cilia types in Drosophila, discovering structural and protein component differences that may be linked to the diversified functions of cilia.
Mitochondria are critical to cellular metabolism, homeostasis and stress responses, and their dysfunction is linked to human disease and pathology. In this issue, we present a Focus of specially commissioned Review articles that discuss recent discoveries and emerging questions in this rapidly advancing field.
Mitochondria sense and respond to many stressors and can support cell survival or death through energy production and signalling pathways. Mitochondrial responses depend on fusion–fission dynamics that dilute and segregate damaged mitochondria. Mitochondrial motility and inter-organellar interactions, such as with the endoplasmic reticulum, also function in cellular adaptation to stress. In this Review, we discuss how stressors influence these components, and how they contribute to the complex adaptive and pathological responses that lead to disease.
Tumours are often more stiff than normal tissue. In this Review, Mohammadi and Sahai discuss recent insights into how such altered tumour mechanics arise and how this affects tumorigenesis.
The metabolic phenotype of tumours is shaped by a complex interplay between cancer cells and their microenvironment. Two studies now show that aspartate acquisition is a metabolic limitation encountered by certain tumours in their native in vivo environment, and that overcoming this limitation is advantageous for tumour growth.
Specific combinations of mutations cause unique signalling and metabolic requirements. Concurrent G-protein αs (GNAS) and KRAS mutations in a subset of pancreatic tumours are now shown to inhibit SIK kinases through aberrant cAMP–PKA activation, triggering a metabolic program defined by lipid metabolism and fatty acid oxidation.
Bardeesy and colleagues show that mutant GNAS suppresses salt-inducible kinases by activating PKA, leading to lipid remodelling and pancreatic tumourigenesis
Lassard et al. demonstrate a relationship between cellular senescence and perturbed ribosome biogenesis and find that the ribosomal protein S14 is an inhibitor of CDK4, inducing an Rb-dependent cell cycle arrest.
Garcia-Bermudez et al. and Sullivan et al. show that endogenous aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours, and that metformin depletes aspartate to limit tumour growth.
Garcia-Bermudez et al. and Sullivan et al. show that endogenous aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours, and that metformin depletes aspartate to limit tumour growth.
The transition from a fertilized egg to a pluripotent and transcriptionally independent embryo requires multi-layered chromatin regulation. A study now provides simultaneous profiling of chromatin accessibility and DNA methylation in human preimplantation embryos at single-cell resolution.
AMPK is a key metabolic sensor promoting cellular energy homeostasis under low-nutrient conditions and other stresses. However, its role in cancer is context-dependent and not fully understood. A study now shows that glioma stem cells co-opt an AMPK-dependent pathway to rewire metabolism, promoting tumour growth.
Using a multi-tier scRNA-seq and CRISP-seq approach, Giladi et al. define a transcriptional signature for the naive haematopoietic stem cell state, and follow progenitor plasticity and fate commitment under the influence of cytokines and growth factors.