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SERCAs are ER transmembrane proteins that pump Ca2+ from the cytosol into the ER lumen to maintain the ER Ca2+ reservoir and regulate cytosolic Ca2+-dependent processes. In preB cells, loss of SERCA2 leads to reduced V(D)J recombination kinetics due to diminished RAG-mediated DNA cleavage. SERCA2 deficiency in B cells leads to increased expression of SERCA3, and combined loss of SERCA2 and SERCA3 results in decreased ER Ca2+ levels, increased cytosolic Ca2+ levels, reduction in RAG1 and RAG2 gene expression, and a profound block in V(D)J recombination. Mice with B cells deficient in SERCA2 and humans with Darier disease, caused by heterozygous ATP2A2 mutations, have reduced numbers of mature B cells. We conclude that SERCA proteins modulate intracellular Ca2+ levels to regulate RAG1 and RAG2 gene expression and V(D)J recombination and that defects in SERCA functions cause lymphopenia.<\/jats:p>","DOI":"10.1084\/jem.20201708","type":"journal-article","created":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T02:29:26Z","timestamp":1620440966000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Sarco\/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8247-8734","authenticated-orcid":true,"given":"Chun-Chin","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 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