Recruitment of BRCA1 limits MYCN-driven accumulation of stalled RNA polymerase

Herold, Steffi; Kalb, Jacqueline; Büchel, Gabriele; Ade, Carsten P.; Baluapuri, Apoorva; Xu, Jiajia; Koster, Jan; Solvie, Daniel; Carstensen, Anne; Klotz, Christina; Rodewald, Sabrina; Schülein-Völk, Christina; Dobbelstein, Matthias; Wolf, Elmar; Molenaar, Jan J.; Versteeg, Rogier; Walz, Susanne; Eilers, Martin

doi:10.1038/s41586-019-1030-9

Cited by 88 publications

(96 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we provide multiple evidences that UF NB-hop tumors up-regulate genes that are involved in different DNA damage response mechanisms, such as DNA repair, double-strand break repair, base-excision repair, and mismatch repair. Concordantly, we report the up-regulation of genes, including BRCA1, BRCA2, CHEK1, CHEK2, and TPX2, which play a regulatory role in the DNA damage response in NB [40][41][42][43][44].…”

Section: Discussionsupporting

confidence: 70%

Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming

Cangelosi

Morini

Zanardi

et al. 2020

Cancers

View full text Add to dashboard Cite

The biological and clinical heterogeneity of neuroblastoma (NB) demands novel biomarkers and therapeutic targets in order to drive the most appropriate treatment for each patient. Hypoxia is a condition of low-oxygen tension occurring in poorly vascularized tumor tissues. In this study, we aimed to assess the role of hypoxia in the pathogenesis of NB and at developing a new clinically relevant hypoxia-based predictor of outcome. We analyzed the gene expression profiles of 1882 untreated NB primary tumors collected at diagnosis and belonging to four existing data sets. Analyses took advantage of machine learning methods. We identified NB-hop, a seven-gene hypoxia biomarker, as a predictor of NB patient prognosis, which is able to discriminate between two populations of patients with unfavorable or favorable outcome on a molecular basis. NB-hop retained its prognostic value in a multivariate model adjusted for established risk factors and was able to additionally stratify clinically relevant groups of patients. Tumors with an unfavorable NB-hop expression showed a significant association with telomerase activation and a hypoxic, immunosuppressive, poorly differentiated, and apoptosis-resistant tumor microenvironment. NB-hop defines a new population of NB patients with hypoxic tumors and unfavorable prognosis and it represents a critical factor for the stratification and treatment of NB patients.

show abstract

Section: Discussionsupporting

confidence: 70%

Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming

Cangelosi

Morini

Zanardi

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…Crystal violet staining was carried out using 0.1% crystal violet in 20% ethanol. Propidium iodide (PI) and annexin V/PI FACS analysis was performed as previously described [62].…”

Section: Fluorescence-activated Cell Sorting (Facs) and Cell Stainingmentioning

confidence: 99%

“…RNA isolation, qPCR and RNA sequencing were performed as described previously [62]. Primers used for qPCR are listed in Supplementary Table 8.…”

Section: Rna Isolation Quantitative Pcr (Qpcr) and Rna-sequencingmentioning

confidence: 99%

A MYC–GCN2–eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer

et al. 2019

Self Cite

View full text Add to dashboard Cite

Data availability RNA-seq data and ribosomal profiling data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE106858. Mass spectrometry data that support the findings of this study have been deposited in figshare.com under the title of this manuscript (A MYC/GCN2/eIF2a negative feedback loop limits protein synthesis to prevent MYC dependent apoptosis in colorectal cancer) by the author Werner Schmitz (

show abstract

“…BRCA1 is generally considered a tumour suppressor involved in DNA repair. However, a recent report outlines a clear oncogenic-like role for BRCA1 in enhancing transcriptional activation by MYCN [29]. MYCN was found to recruit BRCA1 to the promotor-proximal DNA where R-loops arise, thereby promoting mRNA decapping and R-loop resolution.…”

Section: Rbps Involved In Replication Stress and Telomere Maintenancementioning

confidence: 99%

Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

Bell

Hagemann

Holien

et al. 2020

IJMS

View full text Add to dashboard Cite

Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have reported roles in neuroblastoma development and patient outcome, the role of RBPs in neuroblastoma is relatively unstudied. In order to elucidate novel RBPs involved in MYCN-amplified and other high-risk neuroblastoma subtypes, we performed differential mRNA expression analysis of RBPs in a large primary tumour cohort (n = 498). Additionally, we found via Kaplan–Meier scanning analysis that 685 of the 1483 tested RBPs have prognostic value in neuroblastoma. For the top putative oncogenic candidates, we analysed their expression in neuroblastoma cell lines, as well as summarised their characteristics and existence of chemical inhibitors. Moreover, to help explain their association with neuroblastoma subtypes, we reviewed candidate RBPs’ potential as biomarkers, and their mechanistic roles in neuronal and cancer contexts. We found several highly significant RBPs including RPL22L1, RNASEH2A, PTRH2, MRPL11 and AFF2, which remain uncharacterised in neuroblastoma. Although not all RBPs appear suitable for drug design, or carry prognostic significance, we show that several RBPs have strong rationale for inhibition and mechanistic studies, representing an alternative, but nonetheless promising therapeutic strategy in neuroblastoma treatment.

show abstract

Recruitment of BRCA1 limits MYCN-driven accumulation of stalled RNA polymerase

Cited by 88 publications

References 52 publications

Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming

Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming

A MYC–GCN2–eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer

Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

Contact Info

Product

Resources

About