{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T18:04:52Z","timestamp":1763057092468,"version":"3.45.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":16,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC 112-2311-B-005-005","NSTC 113-2311-B-005-002"],"award-info":[{"award-number":["NSTC 112-2311-B-005-005","NSTC 113-2311-B-005-002"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The Nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain is located amino-terminally to the RNA-dependent RNA polymerase (RdRp) in nonstructural protein (nsp)12 of SARS-CoV-2. The GDP-polyribonucleotidyltransferase (GDP-PRNT) and UMPylation activities of NiRAN contribute to viral RNA biogenesis by forming an RNA capping precursor and an RNA synthesis initiation primer, respectively. Translation of nsp12 is mediated by \u22121 programmed ribosomal frameshifting (\u22121 PRF), via an RNA signal composed of a slippery sequence and a downstream stimulator structure. The \u22121 PRF signal encodes a polypeptide, yet its function remains unexplored. Here, we show that the \u22121 PRF signal-encoded polypeptide is required for NiRAN activity. Mutational analysis reveals that a phenylalanine encoded by part of the slippery sequence, as well as two specific amino acids encoded by the stimulator, are essential for the UMPylation and GDP-PRNT activities of NiRAN. Thus, in addition to affecting the expression level of nsp12 through RNA-mediated frameshifting efficiency, variation in the \u22121 PRF signal influences functional viral RNA production through polypeptide-mediated modulation of NiRAN activity. This dual role likely constrains the allowable sequence variation of the \u22121 PRF signal during viral propagation, suggesting that the entire \u22121 PRF signal is a better antiviral target than the stimulator alone.<\/jats:p>","DOI":"10.1093\/narmme\/ugaf037","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T12:25:05Z","timestamp":1760617505000},"source":"Crossref","is-referenced-by-count":0,"title":["Polypeptide encoded by the\u00a0\u22121 PRF signal of SARS-CoV-2 controls multiple enzymatic activities of the viral NiRAN domain"],"prefix":"10.1093","volume":"2","author":[{"given":"Hsiu-Ting","family":"Hsu","sequence":"first","affiliation":[{"name":"Graduate Institute of Biochemistry, National Chung-Hsing University , 145 Xing-Da Road, Taichung 402 ,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Che-Pei","family":"Cho","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biochemistry, National Chung-Hsing University , 145 Xing-Da Road, Taichung 402 ,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Liang","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biochemistry, National Chung-Hsing University , 145 Xing-Da Road, Taichung 402 ,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4469-0387","authenticated-orcid":false,"given":"Kung-Yao","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biochemistry, National Chung-Hsing University , 145 Xing-Da Road, Taichung 402 ,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"2025111313014495900_B1","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/S0022-2836(03)00865-9","article-title":"Unique and conserved features of genome 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