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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,10,22]]},"abstract":"<jats:p>\n                    UBR5 E3 ligase has been associated with cancer susceptibility and neuronal integrity, with functions in chromatin regulation and proteostasis. However, the functions of\n                    <jats:italic>ubr5<\/jats:italic>\n                    within animals remain unclear due to lethality in both mammals and flies when disrupted. Using\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , we show that UBR-5 E3 ligase is required for timely exit of stem fate and complete transition into multiple cell type descendants in an ectodermal blast lineage. Animals lacking intact UBR-5 function simultaneously exhibit both stem fate and differentiated fate in the same descendant cells. A functional screen of UBR-5 physical interactors allowed us to identify the UBE2D2\/3 E2 conjugase LET-70 working with UBR-5 to exit stem fate. Strikingly, we revealed that another UBR-5 physical interactor, namely the nuclear poly(A)-binding protein PABPN1 ortholog PABP-2, worked antagonistically to UBR-5 and LET-70. Lowering\n                    <jats:italic>pabp-2<\/jats:italic>\n                    levels restored normal transition of cell state out of stemness and promoted normal cell fusion when either\n                    <jats:italic>ubr-5<\/jats:italic>\n                    or\n                    <jats:italic>let-70<\/jats:italic>\n                    UBE2D function was compromised. The UBR-5-LET-70 and PABP-2 switch works independently of the stem pool size determined by pluripotency factors like\n                    <jats:italic>lin-28.<\/jats:italic>\n                    UBR-5 limits PABP-2 protein and reverses the PABP-2-dependent gene expression program including developmental, proteostasis, and innate immunity genes. Loss of\n                    <jats:italic>ubr-5<\/jats:italic>\n                    rescues the developmental stall when\n                    <jats:italic>pabp-2<\/jats:italic>\n                    is compromised. Disruption of\n                    <jats:italic>ubr-5<\/jats:italic>\n                    elevates PABP-2 levels and prolongs expression of ectodermal and muscle stem markers at the transition to adulthood. Additionally,\n                    <jats:italic>ubr-5<\/jats:italic>\n                    mutants exhibit an extended period of motility during aging and suppress\n                    <jats:italic>pabp-2-<\/jats:italic>\n                    dependent early onset of immobility.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2407561121","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T13:32:41Z","timestamp":1728999161000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["UBR-5 and UBE2D mediate timely exit from stem fate via destabilization of poly(A)-binding protein PABP-2 in cell state transition"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4440-4475","authenticated-orcid":false,"given":"Jose Francisco","family":"Calva Moreno","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2163-3591","authenticated-orcid":false,"given":"George","family":"Jose","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8993-2001","authenticated-orcid":false,"given":"Yi M.","family":"Weaver","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0830-213X","authenticated-orcid":false,"given":"Benjamin P.","family":"Weaver","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 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F. Calva-Moreno Y. Weaver B. P. Weaver Data from \u201cAlteration of gene expression in ubr-5(-) and pabp-2(RNAi).\u201d NCBI GEO Database. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE261826. 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