Chul Jung

Chemical screening identifies ATM as a target for alleviating senescence

Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATMs role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V1 subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1. Attenuation of ATM activity restored the dimerization, thus consequently facilitating assembly of the V1 and V0 domains with concomitant reacidification of the lysosome. In turn, this reacidification induced the functional recovery of the lysosome/autophagy system and was coupled with mitochondrial functional recovery and metabolic reprogramming. Together, our data reveal a new mechanism through which senescence is controlled by the lysosomal-mitochondrial axis, whose function is modulated by the fine-tuning of ATM activity.

Chemical screening identifies ROCK as a target for recovering mitochondrial function in Hutchinson-Gilford progeria syndrome

Hutchinson‐Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high‐throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho‐associated protein kinase (ROCK) inhibitor (Y‐27632) as an effective agent. To elucidate the underlying mechanism of ROCK in regulating ROS levels, we performed a yeast two‐hybrid screen and discovered that ROCK1 interacts with Rac1b. ROCK activation phosphorylated Rac1b at Ser71 and increased ROS levels by facilitating the interaction between Rac1b and cytochrome c. Conversely, ROCK inactivation with Y‐27632 abolished their interaction, concomitant with ROS reduction. Additionally, ROCK activation resulted in mitochondrial dysfunction, whereas ROCK inactivation with Y‐27632 induced the recovery of mitochondrial function. Furthermore, a reduction in the frequency of abnormal nuclear morphology and DNA double‐strand breaks was observed along with decreased ROS levels. Thus, our study reveals a novel mechanism through which alleviation of the HGPS phenotype is mediated by the recovery of mitochondrial function upon ROCK inactivation.

Enhancement of Mask Selectivity in SiO2 Etching with a Phase-Controlled Pulsed Inductively Coupled Plasma.

We developed a new method to enhace the photoresist selectivity in SiO2 etching by modulating both the source and bias powers and by controlling the phase difference between the modulation functions. Enhancement of mask selectivity was observed in the pulse plasma, especially in the out-phase condition. To understand the heavy polymerization in the out-phase pulse plasma, we analyzed the ion energy distributions of CFx+(x=1, 2, 3) ions using the energy-spectroscopic quadrupole mass spectrometer (QMS) and measured the waveforms of the bias power with a high-voltage probe which was connected directly to the wafer. Two distinct plasma potential distributions were obtained in the pulse plasma and the dc bias voltage (VDC) was maximum in the out-phase condition. The heavy polymerization in the out-phase condition was explained as a result of high VDC. We also investigated the emission intensity of the C2 (516.5 nm) line, and found that C2 species were precursors of the polymerization and contributed to the heavy polymerization in the out-phase condition.