USP11 controls R-loops by regulating senataxin proteostasis

Jurga, Mateusz; Abugable, Arwa A.; Goldman, Alastair S. H.; El‐Khamisy, Sherif F.

doi:10.1038/s41467-021-25459-w

Cited by 19 publications

(10 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Their results suggest that SETX is required to form the asincRNA/R loop “shield” that blocks the repressive effects of sincRNAs. This is in contrasts to other results suggesting that formation of nucleolar R loops is in general enhanced by loss of SETX ( Feng and Manley 2021 ; Jurga et al 2021 ), and that formation of R loops (e.g., involving pRNAs and PAPAS) is associated with silencing rather than enhancement of pre-rRNA transcription ( Zhao et al 2018 ; Feng and Manley 2021 ).…”

Section: Igs Antisense Lncrnas Modulate Rrna Synthesis Via R Loop ‘Sh...contrasting

confidence: 99%

Beyond rRNA: nucleolar transcription generates a complex network of RNAs with multiple roles in maintaining cellular homeostasis

Feng

Manley

2022

Genes Dev.

View full text Add to dashboard Cite

Nucleoli are the major cellular compartments for the synthesis of rRNA and assembly of ribosomes, the macromolecular complexes responsible for protein synthesis. Given the abundance of ribosomes, there is a huge demand for rRNA, which indeed constitutes ∼80% of the mass of RNA in the cell. Thus, nucleoli are characterized by extensive transcription of multiple rDNA loci by the dedicated polymerase, RNA polymerase (Pol) I. However, in addition to producing rRNAs, there is considerable additional transcription in nucleoli by RNA Pol II as well as Pol I, producing multiple noncoding (nc) and, in one instance, coding RNAs. In this review, we discuss important features of these transcripts, which often appear species-specific and reflect transcription antisense to pre-rRNA by Pol II and within the intergenic spacer regions on both strands by both Pol I and Pol II. We discuss how expression of these RNAs is regulated, their propensity to form cotranscriptional R loops, and how they modulate rRNA transcription, nucleolar structure, and cellular homeostasis more generally.

show abstract

Section: Igs Antisense Lncrnas Modulate Rrna Synthesis Via R Loop ‘Sh...contrasting

confidence: 99%

Beyond rRNA: nucleolar transcription generates a complex network of RNAs with multiple roles in maintaining cellular homeostasis

Feng

Manley

2022

Genes Dev.

View full text Add to dashboard Cite

show abstract

“…USP11 has been demonstrated to participate in multiple cellular pathways such as cortical neurogenesis (Chiang et al, 2021), R-loop regulation (Jurga et al, 2021), and DNA repair (Ting et al, 2019). In a proteomic screen, USP11 was identified as a protein that interacts with Beclin-1, VPS34, ATG10, ATG12, and ATG16L1, suggesting that USP11 may function in autophagy (Behrends et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin carboxyl-terminal hydrolase 11 promotes autophagy by de-ubiquitinating and stabilizing Beclin-1

Rao

Song

et al. 2022

GENOME INSTAB. DIS.

View full text Add to dashboard Cite

Autophagy is a major degradation process that degrades and recycles cytoplasmic materials through lysosome for maintaining cellular homeostasis. Dysregulated autophagy is linked with numerous human diseases including cancer. Autophagy marker protein B-cell lymphoma-2 interacting protein 1 (Beclin-1) is essential for autophagosome initiation and maturation. Recently, Ubiquitin carboxyl-terminal hydrolase 11 (USP11) has been reported to promote or inhibit autophagy without identification of any direct target. Here through biochemical reaction in vitro, we demonstrate that USP11 directly interacts with Beclin-1. Both in vitro and in vivo de-ubiquitination assays revealed that USP11 de-ubiquitinates Beclin-1. USP11-mediated de-ubiquitination stabilized Beclin-1 and enhanced the formation of the autophagy-specific class III phosphatidylinositol 3-kinase complexes 1 and 2, thereby promoting autophagy. Together, our results demonstrated that USP11 promotes autophagy under unperturbed conditions by de-ubiquitinating and stabilizing Beclin-1 which may serve as a therapeutic target for autophagy-related diseases.

show abstract

“…SETX was first discovered via ataxia-associated mutations in a human homolog of the yeast gene Sen1 [44] and numerous additional mutations have since been reported that are associated with a rare type of ALS [45,46]. Initial studies showed that SETX helps to remove unintended DNA-RNA hybrid molecules (R-loops) that would otherwise promote genomic instability [47,48]. Interestingly, recent evidence indicates that SETX may be an important regulator of autophagy, especially with respect to the removal of stress granules that form when a cell is starved or under other types of environmental pressure [47].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional targets of senataxin and E2 promoter binding factors are associated with neuro-degenerative pathways during increased autophagic flux

Casey

Liu

Hein

et al. 2022

Preprint

View full text Add to dashboard Cite

Autophagy is an intracellular recycling process that degrades harmful molecules, maintains optimal composition of cellular organelles and enables survival during starvation. Previous studies have demonstrated how transcription factors (TFs) can increase autophagy with therapeutic potential (impaired autophagy in the ageing brain, in particular, may be an important risk factor for dementia). To investigate the transcriptional regulation of autophagy from a systems perspective, we induced autophagy by amino acid starvation and mTOR inhibition in HeLa, HEK 293 and SH-SY5Y cells and used RNA-seq to measure gene expression at three time points. We observed 453 differentially expressed (DE) genes due to starvation and 284 genes due to mTOR inhibition (PFDR < 0.05 in every cell line). Pathway analyses confirmed enrichment of genes implicated in Alzheimer’s (PFDR < 0.001 in SH-SY5Y and HeLa) and Parkinson’s (PFDR ≤ 0.024 in SH-SY5Y and HeLa) diseases and amyotrophic lateral sclerosis (ALS, PFDR < 0.05 in 4 of 6 experiments). We then integrated Signaling Pathway Impact Analysis and TF target enrichment testing to predict which TF target genes were contributing to pathway perturbation. Differential expression of the Senataxin (SETX) target gene set was predicted to activate multiple neurodegenerative pathways (PFDR ≤ 0.04). Notably, SETX is a causal gene for a rare form of ALS. In the SH-SY5Y cells of neuronal origin, the E2F transcription family was predicted to activate Alzheimer’s disease pathway (PFDR ≤ 0.0065). SETX and E2F may be important mediators of transcriptional regulation of autophagy and may provide new therapeutic opportunities for neuro-degenerative conditions.

show abstract

USP11 controls R-loops by regulating senataxin proteostasis

Cited by 19 publications

References 70 publications

Beyond rRNA: nucleolar transcription generates a complex network of RNAs with multiple roles in maintaining cellular homeostasis

Beyond rRNA: nucleolar transcription generates a complex network of RNAs with multiple roles in maintaining cellular homeostasis

Ubiquitin carboxyl-terminal hydrolase 11 promotes autophagy by de-ubiquitinating and stabilizing Beclin-1

Transcriptional targets of senataxin and E2 promoter binding factors are associated with neuro-degenerative pathways during increased autophagic flux

Contact Info

Product

Resources

About