<i>RAD21</i> is a driver of chromosome 8 gain in Ewing sarcoma to mitigate replication stress

Su, Xiaofeng A.; Ma, Duanduan; Parsons, James V.; Replogle, John M.; Amatruda, James F.; Whittaker, Charles A.; Stegmaier, Kimberly; Amon, Angelika

doi:10.1101/gad.345454.120

Cited by 40 publications

(50 citation statements)

References 56 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EWS/FLI has been reported to increase basal transcription in Ewing sarcoma cells resulting in R loop formation ( Gorthi et al., 2018 ). Unresolved R loops can also lead to stalled/collapsed replication forks, DNA damage, and replicative stress in non-transformed primary cells ( Su et al., 2021 ). It is possible that increased R loops and replicative stress are, in part, responsible for the DNA damage phenotype observed with further upregulated EWS/FLI expression by TRIM8 inhibition, the subject of future investigations.…”

Section: Discussionmentioning

confidence: 99%

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

Summary Fusion-transcription factors (fusion-TFs) represent a class of driver oncoproteins that are difficult to therapeutically target. Recently, protein degradation has emerged as a strategy to target these challenging oncoproteins. The mechanisms that regulate fusion-TF stability, however, are generally unknown. Using CRISPR-Cas9 screening, we discovered tripartite motif-containing 8 (TRIM8) as an E3 ubiquitin ligase that ubiquitinates and degrades EWS/FLI, a driver fusion-TF in Ewing sarcoma. Moreover, we identified TRIM8 as a selective dependency in Ewing sarcoma compared with >700 other cancer cell lines. Mechanistically, TRIM8 knockout led to an increase in EWS/FLI protein levels that was not tolerated. EWS/FLI acts as a neomorphic substrate for TRIM8, defining the selective nature of the dependency. Our results demonstrate that fusion-TF protein stability is tightly regulated and highlight fusion oncoprotein-specific regulators as selective therapeutic targets. This study provides a tractable strategy to therapeutically exploit oncogene overdose in Ewing sarcoma and potentially other fusion-TF-driven cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The regulation and function of cohesin may be tissue-specific, and mutations in cohesin are more prominent in certain types of tumors [37]. Recent advances in bladder cancer, colorectal cancer, breast cancer, hepatocellular carcinoma, prostate cancer, and Ewing sarcoma studies have demonstrated that cohesin subunits play a pivotal role in the genesis and development of human tumors [38][39][40][41][42][43]. However, few studies have focused on the significance of cohesin subunits in ESCA.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Values and Underlying Regulatory Network of Cohesin Subunits in Esophageal Carcinoma

Gan¹,

Wang²,

Li³

et al. 2022

J. Cancer

View full text Add to dashboard Cite

Background: Cohesin is a highly conserved and ubiquitously expressed protein complex. While increasing evidence suggests that cohesin dysregulation is vital in the carcinogenesis of numerous malignancies, little is known about the prognostic values and potential mechanisms of cohesin subunits and direct regulators in esophageal carcinoma (ESCA). Methods: RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) were used. The subunits and regulators of cohesin affecting the prognosis of ESCA were screened by Kaplan-Meier survival analysis; univariate and multivariate Cox regression analyses were performed; and the receiver-operating characteristic (ROC) curve was determined. The ESCA hazard model and nomogram map were constructed by integrating the clinical data. We used functional analysis and protein-protein interaction (PPI) networks to explore underlying pathways. Finally, immunohistochemistry was performed to examine the expression levels of cohesin subunits in tissue microarray (TMA). Results: Transcriptome data from multiple ESCA patient datasets showed cohesin subunits SMC1A, SMC1B, SMC3, STAG1, STAG2, RAD21, and cohesin regulators including ESCO2, NIPBL, MAU2, WAPL, PDS5A and PDS5B were all upregulated in ESCA tissues compared to normal tissues. Survival analysis demonstrated that high STAG2 expression was significantly associated with poorer overall survival (OS) and progression-free survival (PFS) in esophageal adenocarcinoma (EAC). In contrast, high RAD21 expression was significantly correlated with better OS in esophageal squamous cell carcinoma (ESCC). Moreover, STAG2 and RAD21 were identified as independent prognostic factors and predictive biomarkers in EAC and ESCC, respectively. Functional enrichment analysis further revealed that STAG2 and RAD21 were mainly involved in the mitotic nuclear division, DNA repair, angiogenesis, epithelial-mesenchymal transition (EMT), and oncogenic signaling pathways. PPI analysis illustrated that STAG2 and RAD21 could cross-talk through cancer-associated modules and performed the core roles of the whole PPI network. Using TMA, STAG2 protein expression positively correlated with lymph node metastasis and advanced clinical stage of EAC patients, whereas there was a negative correlation between RAD21 protein expression and the malignant clinicopathological parameters in ESCC. Conclusion: These findings suggest that STAG2 and RAD21 can be used as predictive biomarkers for risk assessment and prognostic stratification in ESCA, which provide potential novel insights into molecular targets of ESCA.

show abstract

“…By keeping sister chromatids more tightly paired, cohesin could facilitate template switching to repair DNA lesions and promote efficient fork restart [ 47 , 87 ]. In line with such a model, increased expression of the cohesin subunit RAD21 mitigates replication stress in Ewing sarcoma cells [ 176 ]. In addition, cohesin may contribute to promote fork protection and homologous recombination (HR) by the PDS5-dependent recruitment of BRCA2 and RAD51 to stalled replication forks ( Figure 3 B) [ 173 , 177 , 178 ].…”

Section: The Cohesin Complex and Associated Factors In The Dna Replication Stress Responsementioning

confidence: 95%

The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks

Schie

Lange

2021

Cells

View full text Add to dashboard Cite

The cohesin complex facilitates faithful chromosome segregation by pairing the sister chromatids after DNA replication until mitosis. In addition, cohesin contributes to proficient and error-free DNA replication. Replisome progression and establishment of sister chromatid cohesion are intimately intertwined processes. Here, we review how the key factors in DNA replication and cohesion establishment cooperate in unperturbed conditions and during DNA replication stress. We discuss the detailed molecular mechanisms of cohesin recruitment and the entrapment of replicated sister chromatids at the replisome, the subsequent stabilization of sister chromatid cohesion via SMC3 acetylation, as well as the role and regulation of cohesin in the response to DNA replication stress.

show abstract

RAD21 is a driver of chromosome 8 gain in Ewing sarcoma to mitigate replication stress

Cited by 40 publications

References 56 publications

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

Prognostic Values and Underlying Regulatory Network of Cohesin Subunits in Esophageal Carcinoma

The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks

Contact Info

Product

Resources

About