RNA-seq for UBR5 and Cdc73-regulated genes in 4T1 cells treated with Dovitinib
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE222787 | GEO | 2023/01/27
REPOSITORIES: GEO
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Project description:RNA-seq for UBR5 and Cdc73-regulated genes in 4T1 cells treated with Dovitinib
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Project description:RIG-I like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses to numerous RNA viruses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we generated, screened 375 definite ubiquitin ligase knockout cell lines and identified UBR5 as a positive regulator of RLR transcription. UBR5 deficiency (UBR5-/-) reduced antiviral immune responses to RNA viruses, while increased viral replication in primary cells and mice. Ubr5-/- mice were more susceptible to lethal RNA virus infection than Ubr5+/+ littermates. Mechanistically, UBR5 mediated the Lysine 63-linked ubiquitination of TRIM28, an epigenetic repressor of RLRs. This modification prevented intramolecular SUMOylation of TRIM28, thus disengaged the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.
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Project description:UBR5, a HECT-domain E3 ubiquitin ligase, is an attractive therapeutic target for aggressive breast cancers. Defining the substrates of UBR5 is crucial for scientific understanding and clinical intervention. Here, we demonstrate that CDC73, a component of the RNA polymerase II-associated factor 1 complex, is a key substrate that impedes UBR5's profound tumorigenic and metastatic activities in triple-negative breast cancer (TNBC) via mechanisms of regulating the expression of β-catenin and E-cadherin, tumor cell apoptosis and CD8+ T cell infiltration. Expression of CDC73 is also negatively associated with the progression of breast cancer patients. Moreover, we show that UBR5 destabilizes CDC73 by polyubiquitination at Lys243, Lys247, and Lys257 in a non-canonical manner that is dependent on the non-phosphorylation state of CDC73 at Ser465. CDC73 could serve as a molecular switch to modulate UBR5's pro-tumor activities and may provide a potential approach to developing breast cancer therapeutic interventions.
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