{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMethionyl‑tRNA synthetase (MARS) is a pivotal enzyme that catalyzes the attachment of methionine to its cognate tRNA, a fundamental step for initiating protein synthesis. In human cells, MARS possesses an extended N‑terminal region—comprising a glutathione transferase (GST)–like domain along with additional linker segments—that is essential not only for its catalytic activity but also for its integration into the multisynthetase complex, thereby serving as a scaffold for several interacting protein partners. Moreover, MARS undergoes stress‑induced phosphorylation (e.g., via GCN2 activation) that triggers conformational rearrangements, modulating its tRNA binding and facilitating the release of regulatory factors such as the tumor suppressor AIMP3, and thus coupling translational control with cellular DNA repair processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPathogenic mutations in MARS have been linked to a diverse spectrum of human disorders. For instance, heterozygous variants have been implicated in late‑onset axonal Charcot‑Marie‑Tooth disease, whereas biallelic mutations result in more severe multisystem conditions such as pulmonary alveolar proteinosis and interstitial lung and liver disease. In addition, destabilizing mutations that impair tRNA charging have been associated with non‑photosensitive trichothiodystrophy, underscoring how alterations in the enzymatic activity or structural integrity of MARS can manifest in distinct clinical phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in translation, MARS is emerging as a multifaceted regulator with significant clinical implications. Elevated expression of MARS has been associated with protection against reactive oxygen species (ROS) and is linked to tumor growth and drug resistance in non‑small cell lung cancer. In clinical contexts—such as scenarios where limited core tissue is available for diagnostic assessment in lung cancer—the insights into MARS’s dynamic conformational switching and its integration into larger protein complexes may offer new avenues for understanding and eventually modulating its non‑canonical functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ran He, Li-Dong Zu, Peng Yao, et al. 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