Dynamic RNA Modifications in Gene Expression Regulation

A decade has passed since SUMO (small ubiquitin-related modifier) was discovered to be a reversible post-translational protein modifier. During this time many enzymes that participate in regulated SUMO-conjugation and -deconjugation pathways have been identified and characterized. In parallel, the search for SUMO substrates has produced a long list of targets, which appear to be involved in most cellular functions. Sumoylation is a highly dynamic process and its outcomes are extremely diverse, ranging from changes in localization to altered activity and, in some cases, stability of the modified protein. At first glance, these effects have nothing in common; however, it seems that they all result from changes in the molecular interactions of the sumoylated proteins.

Concepts in sumoylation: a decade on

Since the beginning of the century, the mammalian sirtuin protein family (comprising SIRT1-SIRT7) has received much attention for its regulatory role, mainly in metabolism and ageing. Sirtuins act in different cellular compartments: they deacetylate histones and several transcriptional regulators in the nucleus, but also specific proteins in other cellular compartments, such as in the cytoplasm and in mitochondria. As a consequence, sirtuins regulate fat and glucose metabolism in response to physiological changes in energy levels, thereby acting as crucial regulators of the network that controls energy homeostasis and as such determines healthspan.

/pdf/sirtuins-as-regulators-of-metabolism-and-healthspan-jvf88hfgf7.pdf

Sirtuins as regulators of metabolism and healthspan

The nucleolus is a distinct subnuclear compartment that was first observed more than 200 years ago. Nucleoli assemble around the tandemly repeated ribosomal DNA gene clusters and 28S, 18S and 5.8S ribosomal RNAs (rRNAs) are transcribed as a single precursor, which is processed and assembled with the 5S rRNA into ribosome subunits. Although the nucleolus is primarily associated with ribosome biogenesis, several lines of evidence now show that it has additional functions. Some of these functions, such as regulation of mitosis, cell-cycle progression and proliferation, many forms of stress response and biogenesis of multiple ribonucleoprotein particles, will be discussed, as will the relation of the nucleolus to human diseases.

The multifunctional nucleolus

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc- or NAD(+)-dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases.

https://cshperspectives.cshlp.org/content/6/4/a018713.full.pdf?cited-by=yes;6/4/a018713

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

The recently approved KRASG12C inhibitor sotorasib induces durable responses of KRASG12C-mutant non-small cell lung cancers (NSCLCs), however, some patients do not derive benefit. Identification of specific vulnerabilities conferred by co-occurring mutations may enable the development of biomarker-driven combination therapies in distinct subsets of patients. We report that co-occurring loss of STK11/LKB1 is associated with a drug-induced vulnerability of KRAS-mutant NSCLCs to MCL-1 inhibition. In LKB1-deficient cells, inhibition of KRAS-MAPK signaling leads to hyperactivated JNK, which phosphorylates BCL-XL and impairs its ability to sequester BIM, thus creating a dependency on MCL-1 for survival. In LKB1-proficient cells, LKB1 suppresses drug-induced JNK hyperactivation in a NUAK-dependent manner. Ex vivo treatment of tumors from LKB1-deficient but not LKB1 wild-type KRAS-mutant NSCLC patients with sotorasib or trametinib increased MCL-1 dependence. These results uncover a novel role for the LKB1-NUAK axis in regulation of apoptotic dependency and suggest a genotype-directed therapeutic approach for KRAS-LKB1 mutant NSCLC.

/pdf/lkb1-loss-rewires-jnk-induced-apoptotic-protein-dynamics-h3g7oqlt.pdf

LKB1 loss rewires JNK-induced apoptotic protein dynamics through NUAKs and sensitizes KRAS-mutant NSCLC to combined KRASG12C + MCL-1 blockade

Doxorubicin (Dox) is one of the most frequently prescribed anti-cancer drugs. However, treatment with Dox is limited due to cumulative cardiotoxicity. 3-O-β-d-Sophorosylkaempferol-7-O-{3-O-[2(E)-2,6-dimethyl-6-hydroxyocta-2,7-dienoyl]}-α-L-rhamnoside (F-A), kaempferol 3-sophoroside 7-rhamnoside (F-B), and hippophanone (F-C) were successfully obtained by purification and separation of seabuckthorn seed residue in our previous research. This study was undertaken to investigate the protective effect of three flavonoids against Dox-induced H9c2 cell apoptosis. Cell proliferation was detected by MTT assay. 2′,7′-Dichlorofluorescein diacetate (DCFH-DA) was used to determine the production of intracellular reactive oxygen species (ROS). ATP content was measured using an assay kit. Transmission electron microscopy (TEM) was used to observe changes in mitochondrial ultrastructure. The expression levels of proteins (p-JNK, JNK, p-Akt, Akt, p-P38, P38, p-ERK, ERK, p-Src, Src, Sab, IRE1α, Mfn1, Mfn2, and cleaved caspase-3) were evaluated by Western blot. Molecular docking was performed using AutoDock Vina. The three flavonoids could significantly relieve Dox-induced cardiac injury and inhibit cardiomyocyte apoptosis. The mechanisms were mainly related to the stability of mitochondrial structure and function maintained by suppressing the production of intracellular ROS, p-JNK and cleaved caspase-3, and increasing ATP contents and protein expression of mitochondrial mitofusin (Mfn1, Mfn2), Sab and p-Src. Pretreatment with flavonoids from Hippophae rhamnoides Linn. can reduce Dox-induced H9c2 cell apoptosis based on the ‘JNK-Sab-Ros’ signal pathway.

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Flavonoids from Hippophae rhamnoides Linn. Revert Doxorubicin-Induced Cardiotoxicity through Inhibition of Mitochondrial Dysfunction in H9c2 Cardiomyoblasts In Vitro

Jian Ouyang

Papers

LKB1 loss rewires JNK-induced apoptotic protein dynamics through NUAKs and sensitizes KRAS-mutant NSCLC to combined KRASG12C + MCL-1 blockade

Flavonoids from Hippophae rhamnoides Linn. Revert Doxorubicin-Induced Cardiotoxicity through Inhibition of Mitochondrial Dysfunction in H9c2 Cardiomyoblasts In Vitro