DNA Damage Response Protein CHK2 Regulates Metabolism in Liver Cancer

Defective mitosis with chromosome missegregation can have a dramatic effect on genome integrity by causing DNA damage, activation of the DNA damage response (DDR), and chromosomal instability. Although this is an energy-dependent process, mechanisms linking DDR to cellular metabolism are unknown. Here we show that checkpoint kinase 2 (CHK2), a central effector of DDR, regulates cellular energy production by affecting glycolysis and mitochondrial functions. Patients with hepatocellular carcinoma (HCC) had increased CHK2 mRNA in blood, which was associated with elevated tricarboxylic acid cycle (TCA) metabolites. CHK2 controlled expression of succinate dehydrogenase (SDH) and intervened with mitochondrial functions. DNA damage and CHK2 promoted SDH activity marked by increased succinate oxidation through the TCA cycle; this was confirmed in a transgenic model of HCC with elevated DNA damage. Mitochondrial analysis identified CHK2-controlled expression of SDH as key in sustaining reactive oxygen species production. Cells with DNA damage and elevated CHK2 relied significantly on glycolysis for ATP production due to dysfunctional mitochondria, which was abolished by CHK2 knockdown. This represents a vulnerability created by the DNA damage response that could be exploited for development of new therapies

Semi-empirical relationships to assess the seismic performance of slopes from an updated version of the Italian seismic database

Funder: Dipartimento della Protezione Civile, Presidenza del Consiglio dei Ministri; doi: http://dx.doi.org/10.13039/100012783; Grant(s): ReLUIS research project - Working Pachage 16: Geotechnical Engineering - Task Group 2: Slope stabilityAbstractSeismic performance of slopes can be assessed through displacement-based procedures where earthquake-induced displacements are usually computed following Newmark-type calculations. These can be adopted to perform a parametric integration of earthquake records to evaluate permanent displacements for different slope characteristics and seismic input properties. Several semi-empirical relationships can be obtained for different purposes: obtaining site-specific displacement hazard curves following a fully-probabilistic approach, to assess the seismic risk associated with the slope; providing semi-empirical models within a deterministic framework, where the seismic-induced permanent displacement is compared with threshold values related to different levels of seismic performance; calibrating the seismic coefficient to be used in pseudo-static calculations, where a safety factor against limit conditions is computed. In this paper, semi-empirical relationships are obtained as a result of a parametric integration of an updated version of the Italian strong-motion database, that, in turn, is described and compared to older versions of the database and to well-known ground motion prediction equations. Permanent displacement is expressed as a function of either ground motion parameters, for a given yield seismic coefficient of the slope, or of both ground motion parameters and the seismic coefficient. The first are meant to be used as a tool to develop site-specific displacement hazard curves, while the last can be used to evaluate earthquake-induced slope displacements, as well as to calibrate the seismic coefficient to be used in a pseudo-static analysis. Influence of the vertical component of seismic motion on these semi-empirical relationships is also assessed.</jats:p