Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.

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The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma (GBM). Gene set enrichment, LC/MS, and extracellular flux analyses were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency. Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures and in multiple xenograft models ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1 hour, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3β at serine 9. GSK3β promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone-induced apoptosis in stem-like GBM cells and Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction and These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies..

Abstract-Protein kinase A (PKA)-mediated enhancement of L-type calcium currents (I Ca,L ) is essential for sympathetic regulation of the heartbeat and is the classic example of channel regulation by phosphorylation, and its loss is a common hallmark of heart failure. Mechanistic understanding of how distinct Ca V channel subunits contribute to PKA modulation of I Ca,L has been intensely pursued yet remains elusive. Moreover, critical features of this regulation such as its functional reserve (the surplus capacity available for modulation) in the heart are unknown. Here, we use an overexpression paradigm in heart cells to simultaneously identify the impact of auxiliary Ca V ␤s on PKA modulation of I Ca,L and to gauge the functional reserve of this regulation in the heart. Ca V 1.2 channels containing wild-type ␤ 2a or a phosphorylationdeficient mutant (␤ 2a,AAA ) were equally upregulated by PKA, discounting a necessary role for ␤ phosphorylation. Nevertheless, channels reconstituted with ␤ 2a displayed a significantly diminished PKA response compared with other ␤ isoforms, an effect explainable by a uniquely higher basal P o of ␤ 2a channels. Overexpression of all ␤s increased basal current density, accompanied by a concomitant decrease in the magnitude of PKA regulation. Scatter plots of fold increase in current against basal current density revealed an inverse relationship that was conserved across species and conformed to a model in which a large fraction of channels remained unmodified after PKA activation. These results redefine the role of ␤ subunits in PKA modulation of Ca V 1.2 channels and uncover a new design principle of this phenomenon in the heart, vis à vis a limited functional reserve. (Circ Res. 2008;102:e54-e64.)2) channels are important determinants of cardiac excitability and indispensable for excitationcontraction coupling in the heart. 1 Fitting with their central role in cardiac biology, tuning Ca V 1.2 channel activity is a prominent method for physiological and therapeutic regulation of the heartbeat. 2 A classic example of physiological modulation is the upregulation of cardiac Ca V 1.2 channel activity in response to ␤-adrenergic receptor stimulation, an effect mediated through activation of protein kinase A (PKA). [2][3][4] This phenomenon is an important contributor to sympathetic regulation of the heartbeat, and its loss is a harmful hallmark of heart failure. 2,5 PKA-mediated regulation of cardiac Ca V 1.2 channels represents the original example of channel modulation by phosphorylation, and mechanistic understanding of this phenomenon has been widely pursued for more than 3 decades. 3,4,6 Despite years of intense study, many key features of how activated PKA upregulates Ca V 1.2 channel activity remain unknown. Native Ca V 1.2 channels are comprised minimally of a pore-forming ␣ 1C protein assembled in a 1:1 ratio with auxiliary Ca V ␤ and ␣ 2 ␦ subunits. 2,7 Ca V ␤ subunits are necessary for trafficking Ca V ␣ 1 to the plasma membrane and also greatly influence channel gating prope...