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Here we hypothesize that such mechanisms are relevant to routine storage in the blood bank.<\/jats:p><\/jats:sec><jats:sec><jats:title>STUDY DESIGN AND METHODS<\/jats:title><jats:p>Within the framework of the REDS\u2010III RBC\u2010Omics (Recipient Epidemiology Donor Evaluation Study III Red Blood Cell\u2010Omics) study, packed RBC units (n = 599) were stored under blood bank conditions for 10, 23, and 42 days and profiled for oxidative hemolysis and time\u2010dependent metabolic dysregulation of the trans\u2010sulfuration pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>In these units, methionine consumption positively correlated with storage age and oxidative hemolysis. Mechanistic studies show that this phenomenon is favored by oxidative stress or hyperoxic storage (sulfur dioxide &gt;95%), and prevented by hypoxia or methyltransferase inhibition. Through a combination of proteomics approaches and <jats:sup>13<\/jats:sup>C\u2010methionine tracing, we observed oxidation\u2010induced increases in both Asn deamidation to Asp and formation of methyl\u2010Asp on key structural proteins and enzymes, including Band 3, hemoglobin, ankyrin, 4.1, spectrin beta, aldolase, glyceraldehyde 3\u2010phosphate dehydrogenase, biphosphoglycerate mutase, lactate dehydrogenase and catalase. Methylated regions tended to map proximal to the active site (e.g., N316 of glyceraldehyde 3\u2010phosphate dehydrogenase) and\/or residues interacting with the N\u2010terminal cytosolic domain of Band 3.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>While methylation of basic amino acid residues serves as an epigenetic modification in nucleated cells, protein methylation at carboxylate side chains and deamidated asparagines is a nonepigenetic posttranslational sensor of oxidative stress and refrigerated storage in anucleated human RBCs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/trf.14936","type":"journal-article","created":{"date-parts":[[2018,10,12]],"date-time":"2018-10-12T21:41:34Z","timestamp":1539380494000},"page":"2978-2991","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Methylation of protein aspartates and deamidated asparagines as a function of blood bank storage and oxidative stress in human red blood cells"],"prefix":"10.1111","volume":"58","author":[{"given":"Julie A.","family":"Reisz","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics University of Colorado Denver\u2013Anschutz Medical Campus  Aurora Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Nemkov","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics University of Colorado Denver\u2013Anschutz Medical Campus  Aurora Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Dzieciatkowska","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics University of Colorado Denver\u2013Anschutz Medical Campus  Aurora Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Culp\u2010Hill","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics University of Colorado Denver\u2013Anschutz Medical Campus  Aurora Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Stefanoni","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics University of Colorado Denver\u2013Anschutz Medical Campus  Aurora Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan C.","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics University of Colorado Denver\u2013Anschutz Medical Campus  Aurora Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuro","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Hemanext Inc.  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