UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability

Tsai, Jonathan M.; Aguirre, Jacob D.; Li, Yen-Der; Brown, Jared; Focht, Vivian; Kater, Lukas; Kempf, Georg; Sandoval, Brittany; Schmitt, Stefan; Rutter, Justine C.; Galli, Pius; Sandate, Colby R.; Cutler, Jevon; Zou, Charles; Donovan, Katherine A.; Lumpkin, Ryan; Cavadini, Simone; Park, Paul M.C.; Sievers, Quinlan L.; Hatton, Colman J.; Ener, Elizabeth T.; Sperling, Micah T.; Słabicki, Mikołaj; Kim, Jeonghyeon; Zon, Rebecca L.; Zhang, Zinan; Miller, Peter G.; Belizaire, Roger; Sperling, Adam S.; Fischer, Eric S.; Irizarry, Rafael A.; Armstrong, Scott A.; Thomä, Nicolas H.; Ebert, Benjamin L.

doi:10.1016/j.molcel.2023.06.028

Cited by 21 publications

(17 citation statements)

References 101 publications

(116 reference statements)

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“…While no drastic changes in the cellular abundance of KI Halo-tagged RARα or RXRα was observed in the presence of SNAP, SNAP-RXRα or RARα RR -SNAP proteins, the abundance of KI Halo-tagged RARα was approximately halved when RARα-SNAP was overexpressed (Figure 2E and S5B). This is likely distinct from previously reported ligand dependent RARα degradation (Tsai et al, 2023; Zhu et al, 1999) (see Discussion).…”

Section: Resultscontrasting

confidence: 95%

“…It is possible that endogenous RAR may be more readily degraded when not bound by RXR, analogous to what was recently shown for the c-MYC/MAX heterodimers (Mark et al, 2023). Second, as has been previously reported, RARα expression decreases upon ligand treatment (Ismail and Nawaz, 2005; Kopf et al, 2000; Osburn et al, 2001; Tsai et al, 2023; Zhu et al, 1999). Curiously, a 50% reduction in RARα upon addition of ligand did not affect the f bound of either RARα or RXRα (Figure S3A and S3B), suggesting that most chromatin binding of endogenous RXRα in U2OS cells depends on heterodimerization partners other that RARα (see Table S1)…”

Section: Discussionsupporting

confidence: 60%

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Surprising Features of Nuclear Receptor Interaction Networks Revealed by Live Cell Single Molecule Imaging

Dahal,

Graham,

Dailey

et al. 2023

Preprint

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Type 2 Nuclear Receptors (T2NRs) require heterodimerization with a common partner, the Retinoid X Receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and over-expression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged retinoid X receptor (RXR) and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.

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Section: Resultscontrasting

confidence: 95%

Section: Discussionsupporting

confidence: 60%

Surprising Features of Nuclear Receptor Interaction Networks Revealed by Live Cell Single Molecule Imaging

Dahal,

Graham,

Dailey

et al. 2023

Preprint

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“…While we identified UBR5 as the E3 ligase that targets Rb for degradation, we want to emphasize that Rb is not the sole target of UBR5. Multiple papers have shown that UBR5 has other targets including MYC, Nuclear hormone receptors, and SPT4/5 [51][52][53] . Here, we identify Rb as an additional target of UBR5.…”

Section: Discussionmentioning

confidence: 99%

“…From this screen, we only identified UBR5 as specifically targeting un-phosphorylated Rb for degradation (Figure 4D; Figure S10A, B). UBR5 is a verified E3 ubiquitin ligase belonging to the HECT family known to play roles in transcription and the DNA damage response [50][51][52][53] . However, Rb has never been reported to be a substrate of UBR5.…”

Section: The Degradation Of Un-or Hypo-phosphorylated Rb Is Mediated ...mentioning

confidence: 99%

The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5

Zhang,

Valenzuela,

Zatulovskiy

et al. 2023

Preprint

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Mammalian cells make the decision to divide at the G1/S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Rb is inhibited by two parallel pathways. In the canonical pathway, cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, Rb’s concentration decreases during G1 through an unknown mechanism. Here, we found that regulated protein degradation via the E3 ubiquitin ligase UBR5 is responsible for Rb’s concentration drop in G1.UBR5knockout cells have increased Rb concentration in early G1, exhibited a lower G1/S transition rate, and are more sensitive to inhibition of Cdk4/6. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.One-Sentence SummaryThe E3 ligase UBR5 progressively reduces the concentration of the retinoblastoma protein Rb during G1 to drive proliferation.

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“…The three identified A3-targeting E3 ligases UBR5 [87][88][89][90][91][92] , HUWE 71,72,[93][94][95][96][97][98] , and UBR4 56,74,87,[99][100][101][102][103][104][105] , have previously been linked to the turn-over of a diverse array of substrates, thereby exerting control over numerous cellular processes. This suggests that these E3 ligases possess the ability to identify multiple substrate classes based on broad biochemical or biophysical characteristics.…”

Section: Substrate Preference and Cooperativity Of Ubr4 Ubr5 And Huwe1mentioning

confidence: 99%

Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity

Schwartz,

Budroni,

Meyenberg

et al. 2024

Preprint

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Members of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family play crucial roles as antiviral restriction factors, yet some APOBEC3 (A3) members drive harmful hypermutation in humans, contributing to cancer. The cancer-associated A3 proteins are capable to transit from the cytosol to nucleus, driving genome mutations. Here, we show that the major cancer-associated members are efficiently removed by the ubiquitin-proteasome pathway, pointing to distinct cellular pathways protecting genomic DNA from hypermutation. Through genetic and proteomic screening UBR4, UBR5, and HUWE1 were identified as the ubiquitin E3 ligases marking cancer-associated A3B and A3H-I for degradation, thereby limiting A3-driven hypermutation. Mechanistically, UBR5 and HUWE1 recognize the unoccupied A3 RNA-binding domain, promoting proteasomal degradation. Depletion or mutation of the E3 ligases in cell models and cancer samples increased A3-driven genome mutagenesis. Our findings reveal UBR4, UBR5, and HUWE1 as crucial factors of a ubiquitination cascade maintaining human genome stability.

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UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability

Cited by 21 publications

References 101 publications

Surprising Features of Nuclear Receptor Interaction Networks Revealed by Live Cell Single Molecule Imaging

Surprising Features of Nuclear Receptor Interaction Networks Revealed by Live Cell Single Molecule Imaging

The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5

Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity

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