bims-iorami 2024-01-28 papers

Issue of 2024‒01‒28
two papers selected by
Chenxiao Yu, Soochow University

Heliyon. 2024 Jan 15. 10(1): e24029

Advances in crosstalk among innate immune pathways activated by mitochondrial DNA.

Guangwei Tao, Wenyan Liao, Jiafeng Hou, Xinmiao Jiang, Xin Deng, Guodong Chen, Chengming Ding.

Mitochondria are not only the power plant for intracellular oxidative phosphorylation and ATP synthesis, but also involved in cell proliferation, differentiation, signaling and apoptosis. Recent studies have shown that mitochondria play an important role in other pathophysiological functions in addition to cellular energy metabolism. Mitochondria release mitochondrial DNA (mtDNA) as a damage-associated molecular pattern (DAMP) to activate Toll-like receptor 9 (TLR9), NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune signaling pathways against foreign pathogenic microorganisms. The innate immune response not only promotes antimicrobial immune defense and regulates antiviral signaling, but their overactivation also induces the onset and progression of inflammatory diseases. In this paper, we review the role of mtDNA in the activation of innate immune signaling pathways and the crosstalk among innate immune signaling pathways activated by mtDNA, providing clues for the study of inflammatory diseases caused by mtDNA cytoplasmic translocation.

Keywords: NLRP3 inflammasome; TLR9; cGAS-STING signaling pathway; mtDNA

DOI: https://doi.org/10.1016/j.heliyon.2024.e24029

Mol Cancer. 2024 Jan 23. 23(1): 21

The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway.

Konstantinos Karakostis, Laurence Malbert-Colas, Aikaterini Thermou, Borek Vojtesek, Robin Fåhraeus.

BACKGROUND: The ATM kinase constitutes a master regulatory hub of DNA damage and activates the p53 response pathway by phosphorylating the MDM2 protein, which develops an affinity for the p53 mRNA secondary structure. Disruption of this interaction prevents the activation of the nascent p53. The link of the MDM2 protein-p53 mRNA interaction with the upstream DNA damage sensor ATM kinase and the role of the p53 mRNA in the DNA damage sensing mechanism, are still highly anticipated.METHODS: The proximity ligation assay (PLA) has been extensively used to reveal the sub-cellular localisation of the protein-mRNA and protein-protein interactions. ELISA and co-immunoprecipitation confirmed the interactions in vitro and in cells.
RESULTS: This study provides a novel mechanism whereby the p53 mRNA interacts with the ATM kinase enzyme and shows that the L22L synonymous mutant, known to alter the secondary structure of the p53 mRNA, prevents the interaction. The relevant mechanistic roles in the DNA Damage Sensing pathway, which is linked to downstream DNA damage response, are explored. Following DNA damage (double-stranded DNA breaks activating ATM), activated MDMX protein competes the ATM-p53 mRNA interaction and prevents the association of the p53 mRNA with NBS1 (MRN complex). These data also reveal the binding domains and the phosphorylation events on ATM that regulate the interaction and the trafficking of the complex to the cytoplasm.
CONCLUSION: The presented model shows a novel interaction of ATM with the p53 mRNA and describes the link between DNA Damage Sensing with the downstream p53 activation pathways; supporting the rising functional implications of synonymous mutations altering secondary mRNA structures.

Keywords: DNA Damage Sensing; Genotoxic stress; MDM2; MRN complex; Precision medicine; RNA secondary structure; Synonymous mutations

DOI: https://doi.org/10.1186/s12943-024-01933-z