PubMed · 4356793
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R I Gvozdev, A P Sadkov, A I Kotel'nikov, G I Likhtenshteĭn. [Catalytically active nitrogenase centers].. https://pubmed.ncbi.nlm.nih.gov/4356793/
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The human mitochondrial genome must be replicated and expressed in a timely manner to maintain energy metabolism and supply cells with adequate levels of adenosine triphosphate. Central to this process is the idea that replication primers and gene products both arise via transcription from a single light strand promoter (LSP) such that primer formation can influence gene expression, with no consensus as to how this is regulated. Here, we report the discovery of a second light strand promoter (LSP2) in humans, with features characteristic of a bona fide mitochondrial promoter. We propose that the position of LSP2 on the mitochondrial genome allows replication and gene expression to be orchestrated from two distinct sites, which expands our long-held understanding of mitochondrial gene expression in humans.
Small-molecule kinase inhibitors represent a major group of cancer therapeutics, but tumor responses are often incomplete. To identify pathways that modulate kinase inhibitor response, we conducted a genome-wide knockout (KO) screen in glioblastoma cells treated with the pan-ErbB inhibitor neratinib. Loss of general control nonderepressible 2 (GCN2) kinase rendered cells resistant to neratinib, whereas depletion of the GADD34 phosphatase increased neratinib sensitivity. Loss of GCN2 conferred neratinib resistance by preventing binding and activation of GCN2 by neratinib. Several other Food and Drug Administration (FDA)-approved inhibitors, such erlotinib and sunitinib, also bound and activated GCN2. Our results highlight the utility of genome-wide functional screens to uncover novel mechanisms of drug action and document the role of the integrated stress response (ISR) in modulating the response to inhibitors of oncogenic kinases.
Cystic fibrosis (CF) is characterized by abnormal regulation of epithelial ion and fluid transport due to mutations in the CF transmembrane conductance regulator (CFTR), an apical membrane-localized Cl- channel, that usually prevent it from exiting the endoplasmic reticulum. Defective or absent CFTR in the epithelium is believed to disrupt fluid balance in human airways and thereby contribute to chronic respiratory inflammation. Patch-clamp of the plasma membrane and outer membrane of the nuclear envelope of nuclei isolated from CFTR-expressing Chinese hamster ovary cells revealed that CFTR is associated with a regulated ATP channel in both membrane compartments. CFTR expression was also shown to be associated with permeability to another adenine nucleotide, adenosine 3'-phosphate 5'-phosphosulfate, the universal sulfate donor in cells. These results may provide a link between the ion channel function of CFTR and abnormal glycoprotein processing observed in CF.