An RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations

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dc.coverageDOI: 10.1126/scisignal.abm5995
dc.creatorSegarra-Fas, Anna
dc.creatorEspejo-Serrano, Carmen
dc.creatorBustos, Francisco
dc.creatorZhou, Houjiang
dc.creatorWang, Feng
dc.creatorToth, Rachel
dc.creatorMacartney, Thomas
dc.creatorBach, Ingolf
dc.creatorNardocci, Gino
dc.creatorFindlay, Greg M.
dc.date2022
dc.date.accessioned05-01-2026 18:20
dc.date.available05-01-2026 18:20
dc.description<p>The E3 ubiquitin ligase RNF12 plays essential roles during development, and the gene encoding it, RLIM, is mutated in the X-linked human developmental disorder Tonne-Kalscheuer syndrome (TOKAS). Substrates of RNF12 include transcriptional regulators such as the pluripotency-associated transcriptional repressor REX1. Using global quantitative proteomics in male mouse embryonic stem cells, we identified the deubiquitylase USP26 as a putative downstream target of RNF12 activity. RNF12 relieved REX1-mediated repression of Usp26, leading to an increase in USP26 abundance and the formation of RNF12-USP26 complexes. Interaction with USP26 prevented RNF12 autoubiquitylation and proteasomal degradation, thereby establishing a transcriptional feed-forward loop that amplified RNF12-dependent derepression of REX1 targets. We showed that the RNF12-USP26 axis operated specifically in mouse testes and was required for the expression of gametogenesis genes and for germ cell differentiation in vitro. Furthermore, this RNF12-USP26 axis was disrupted by RLIM and USP26 variants found in TOKAS and infertility patients, respectively. This work reveals synergy within the ubiquitylation cycle that controls a key developmental process in gametogenesis and that is disrupted in human genetic disorders.</p>eng
dc.identifierhttps://investigadores.uandes.cl/en/publications/92c6a139-9084-4574-953f-0585d0dda969
dc.languageeng
dc.rightsinfo:eu-repo/semantics/openAccess
dc.sourcevol.15 (2022) date: 2022-07-12 nr.742
dc.titleAn RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutationseng
dc.typeArticleeng
dc.typeArtículospa
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