bims-iorami 2024-01-07 papers

Issue of 2024‒01‒07
two papers selected by
Chenxiao Yu, Soochow University

Int J Radiat Biol. 2024 Jan 03. 1-11

Nuclear DNA damage-triggered ATM-dependent AMPK activation regulates the mitochondrial radiation response.

Tsutomu Shimura, Kenta Sunaga, Mayu Yamazaki, Nara Honoka, Megumi Sasatani, Kenji Kamiya, Akira Ushiyama.

PURPOSE: AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and is essential for controlling mitochondrial homeostasis. Here, we investigated the regulatory mechanisms involved in AMPK activation to elucidate how networks of intracellular signaling pathways respond to stress conditions.MATERIALS AND METHODS: Inhibitors of ATM, DNA-PK, and AKT were tested in normal TIG-3 and MRC-5 human fibroblasts to determine which upstream kinases are responsible for AMPK activation. SV40 transformed-human ATM-deficient fibroblasts (AT5BIVA) and their ATM-complemented cells (i.e., AT5BIVA/ATMwt) were also used. Protein expression associated with AMPK signaling was examined by immunostaining and/or Western blotting.
RESULTS: Radiation-induced nuclear DNA damage activates ATM-dependent AMPK signaling pathways that regulate mitochondrial quality control. In contrast, hypoxia and glucose starvation caused ATP depletion and activated AMPK via a pathway independent of ATM. DNA-PK and AKT are not involved in AMPK-mediated mitochondrial signaling pathways.
CONCLUSION: Activation of the AMPK signaling pathway differs depending on the stimulus. Radiation activates AMPK through two pathways: depletion of ATP-mediated LKB1 signaling and nuclear DNA damage-induced ATM signaling. Nuclear DNA damage signaling to mitochondria therefore plays a pivotal role in determining the cell fates of irradiated cells.

Keywords: AMPK; ATM; Mitochondria; glucose starvation; hypoxia; radiation

DOI: https://doi.org/10.1080/09553002.2023.2295297

bioRxiv. 2023 Dec 15. pii: 2023.12.14.571787. [Epub ahead of print]

Inhibition of O -GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.

Jianwen Chen, Bao Zhao, Tianliang Li, Hong Dong, Xiang Cheng, Wang Gong, Jing Wang, Junran Zhang, Gang Xin, Yanbao Yu, Yu L Lei, Jennifer D Black, Zihai Li, Haitao Wen.

The O -GlcNAc transferase (OGT) is an essential enzyme that mediates protein O -GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O -GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT ( Ogt -/- ) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the Apc gene ( Apc min ). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt -/- cancer cells restored tumor growth, and this correlated with impaired CD8 + T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.

DOI: https://doi.org/10.1101/2023.12.14.571787