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We previously showed that tyrosyl\u2010tRNA synthetase (TyrRS\/YARS1) is reduced in Alzheimer's Disease (AD) brains, and tyrosine and phenylalanine decrease TyrRS in neurons. Here, we found that tau is a negative regulator, whereas estrogen and leucine act as positive regulators of TyrRS. Young female mice exhibit increased TyrRS in the cortex compared to male mice. Notably, young <jats:italic>Tau<\/jats:italic> knockout male, but not female mice showed increased cortical TyrRS. Tau accumulation in middle\u2010aged female mice did not decrease cortical TyrRS compared to males, suggesting that middle\u2010aged females are resilient to tau\u2010mediated TyrRS depletion. Tyrosine and phenylalanine treatment decreased tubulin tyrosination, activated DNA repair pathways, and protected against etoposide (ETO) and camptothecin (CPT)\u2010induced toxicity, respectively, in neurons. While tyrosine facilitated topoisomerase 1 (TOP1) recruitment to chromatin and inhibited global transcription, in contrast, phenylalanine recruited topoisomerase 2 beta (TOP2\u03b2) to chromatin and stimulated global transcription. Furthermore, tyrosine decreased the presence of DNA fragments in a comet assay whereas phenylalanine increased them. Addition of <jats:italic>cis<\/jats:italic>\u2010resveratrol (<jats:italic>cis<\/jats:italic>\u2010RSV) protected against tyrosine\u2010induced transcription inhibition by facilitating the recruitment of both TOP1 and TOP2\u03b2 to chromatin and increasing tubulin tyrosination. Moreover, <jats:italic>cis<\/jats:italic>\u2010RSV decreased both total and phosphorylated tau and protected neurons against amyloid beta (A\u03b2)\u2010induced neurite degeneration and DNA damage. Gene expression profiling using human embryonic stem cell (hESC)\u2010derived neurons demonstrated that <jats:italic>cis<\/jats:italic>\u2010RSV is a broad\u2010spectrum neuroprotective and anti\u2010viral agent. In contrast, <jats:italic>trans<\/jats:italic>\u2010RSV mimics phenylalanine\u2010induced gene expression, including downregulation of long genes and induction of an AD\u2010like gene expression signature. This work suggests that age and disease\u2010associated increases in serum tyrosine and phenylalanine levels would activate neuronal DNA repair while inhibiting transcription and tubulin tyrosination. <jats:italic>cis<\/jats:italic>\u2010RSV protects against their toxicity by restoring tubulin tyrosination, TOP1 and TOP2\u03b2\u2010mediated transcription, and decreasing tau in primary neurons.<\/jats:p>","DOI":"10.1002\/iub.70030","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T08:06:18Z","timestamp":1750147578000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tyrosine and Phenylalanine Activate Neuronal <scp>DNA<\/scp> Repair but Exhibit Opposing Effects on Global Transcription and Adult Female Mice Are Resilient to <scp>TyrRS<\/scp>\/<scp>YARS1<\/scp> Depletion"],"prefix":"10.1002","volume":"77","author":[{"given":"Megha","family":"Jhanji","sequence":"first","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences, College of Pharmacy University of South Carolina  Columbia South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashita","family":"Bhan","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences, College of Pharmacy University of South Carolina  Columbia South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Arrowood","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina W.","family":"Yakout","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Center for Behavioral Neuroscience Georgia State University  Atlanta Georgia 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Columbia South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia B.","family":"Lizarraga","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology, and Biochemistry, and Center for Translational Neuroscience Brown University  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taras Y.","family":"Nazarko","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela M.","family":"Mabb","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Center for Behavioral Neuroscience Georgia State University  Atlanta Georgia 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