{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T23:13:08Z","timestamp":1783638788963,"version":"3.55.0"},"posted":{"date-parts":[[2025,12,18]]},"group-title":"Molecular Biology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH","award":["CA275184"],"award-info":[{"award-number":["CA275184"]}]},{"name":"NIH","award":["CA271595"],"award-info":[{"award-number":["CA271595"]}]},{"name":"NIH","award":["R35GM145279"],"award-info":[{"award-number":["R35GM145279"]}]},{"name":"NIH","award":["R01NS125018"],"award-info":[{"award-number":["R01NS125018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Accurate pre-mRNA splicing is essential for the transfer of genetic information but faces unique challenge in higher primates due to the massive expansion of intronic Alu elements\n                  <jats:sup>1\u20133<\/jats:sup>\n                  . While studying Ku, the Ku70\/Ku80 heterodimer best known for initiating non-homologous end-joining (NHEJ) by encircling DNA ends\n                  <jats:sup>4<\/jats:sup>\n                  , we discovered that Ku expression increased markedly during primate evolution in parallel with Alu expansion\n                  <jats:sup>5<\/jats:sup>\n                  . Ku binds double-stranded RNA (dsRNA) stem-loops, including those at the antisense Alu (asAlu) elements within introns\n                  <jats:sup>5<\/jats:sup>\n                  . Here, we show that Ku-depletion in human cells has a broad impact on splicing largely independent of cell-cycle states, NHEJ, or innate immune signaling, significantly affecting ~8-10% of quantifiable alternative splicing events. Mechanistically, Ku directly binds exonic asAlu to prevent their aberrant inclusion and binds asAlu within inverted-repeat Alu (irAlu) pairs flanking canonical exons to prevent exon skipping\n                  <jats:sup>6<\/jats:sup>\n                  . Among human tissues, Ku expression in the brain is consistently ~50% lower, correlating with more permissive expression of Alu-derived splice variants, particularly those encoding mitochondrial proteins and RNA-binding factors. Correspondingly, heterozygous Ku loss in patient causes developmental delay, neurological dysfunction, and acidosis. Together our findings identified Ku as a critical suppressor of Alu-associated alternative splicing co-opted during evolution with implications for primate brain function and human disease.\n                <\/jats:p>","DOI":"10.64898\/2025.12.17.694518","type":"posted-content","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T15:40:11Z","timestamp":1766072411000},"source":"Crossref","is-referenced-by-count":2,"title":["Primate-specific adaptation of Ku protects transcriptomic integrity by suppressing Alu-mediated alternative splicing"],"prefix":"10.64898","author":[{"given":"Tianji","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimin","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimeng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel 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