A Recurrent RECQL4 Mutation in Rothmund-Thomson Syndrome Impairs Protein Function by Altering Transcript Splicing
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ABSTRACT:
PROVIDER: PRJNA670358 | ENA |
REPOSITORIES: ENA
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Project description:This study was performed to provide a detailed understanding of the functions and pathways that intersect with the essential DNA replication factor RECQL4. Mutations in RECQL4 cause Rothmund-Thomson Syndrome (RTS), a familial cancer syndrome associated with early onset osteosarcoma in a high proportion of patients. Using murine RECQL4 mutations that closely map to recurrent human RTS mutations, we performed an unbiased genome-wide screen to identify genes that, when deleted, rescued the phenotypes associated with RECQL4 mutation.
2025-11-27 | GSE273174 | GEO
Project description:This study was performed to provide a detailed understanding of the functions and pathways that intersect with the essential DNA replication factor RECQL4. Mutations in RECQL4 cause Rothmund-Thomson Syndrome (RTS), a familial cancer syndrome associated with early onset osteosarcoma in a high proportion of patients. Using murine RECQL4 mutations that closely map to recurrent human RTS mutations, we performed an unbiased genome-wide screen to identify genes that, when deleted, rescued the phenotypes associated with RECQL4 mutation.
2025-11-27 | GSE273006 | GEO
Project description:RECQL4, a member of the RecQ helicase family, plays a role in maintaining genomic stability, but its precise function remains unclear. The N-terminus of RECQL4 has similarity to Sld2, a protein required for the firing of DNA replication origins in budding yeast. Consistent with this sequence similarity, Xenopus RECQL4 has been implicated in initiating DNA replication in oocyte extracts. To determine whether human RECQL4 is required for firing of DNA replication origins, we generated cells in which both RECQL4 alleles were targeted, resulting in either lack of protein expression (Knock-Out) or expression of a full-length, mutant protein lacking helicase activity (Helicase Dead). Surprisingly, both the RECQL4 Knock-Out and Helicase Dead cells were viable and exhibited essentially identical origin firing profiles as the parental cells. Analysis of the rate of fork progression revealed normal rates in the RECQL4 Knock Out cells, but decreased rates in the RECQL4 inactive cells. Thus, while budding yeast Sld2 is required for DNA replication origin firing, our evidence suggest that human RECQL4 has assumed a role in the regulation of replication fork progression.
2024-04-17 | GSE225532 | GEO
Project description:The high frequency of somatic copy number alterations, as opposed to point mutations, is considered a unique feature of high-grade serous ovarian carcinoma (HGSOC). Amplification-dependent overexpression of RECQL4, which participates in DNA replication and repair, mediates the development of various cancers, but its pathobiological and clinical roles are poorly understood. Here, using bioinformatics analysis, RECQL4 amplification was found to occur in 27% of HGSOC samples in the TCGA cohort. RECQL4 was found to be upregulated and associated with a poor prognosis based on the immunohistochemistry staining of HGSOC. Functionally, RECQL4 overexpression increased proliferation and invasion of ovarian cancer cells both in vitro and in vivo. RECQL4 silencing had the opposite effects. In addition, RECQL4 knockdown enhanced the sensitivity of ovarian cancer cells to cisplatin and PARP inhibitor (PARPi). Further mechanistic investigations revealed that MAFB was a downstream target of RECQL4. The oncogenic effect of RECQL4 was attenuated after MAFB knockdown. Moreover, RECQL4 overexpression was negatively regulated by the tumour suppressor miR-10a-5p. Collectively, these findings indicate that genomic amplification and low expression of miR-10a-5p contribute to RECQL4 overexpression in ovarian cancer. This is the first study to reveal the oncogenic functions and clinical significance of RECQL4 in ovarian cancer.
2020-10-13 | GSE153839 | GEO
Project description:Osteosarcoma is the most common malignancy of bone, and occurs most frequently in children and adolescents. Currently, the most reliable technique for prognostication is measuring histopathologic tumor necrosis following preoperative chemotherapy, and favourable prognosis is signified by 90% or greater estimated necrosis of the tumour. Neither genetic testing nor molecular biomarkers have been described for this tumour. We used the novel nanoString mRNA expression analysis system to analyzed total RNA from 35 flash-frozen sporadic paediatric osteosarcoma biopsy and resection specimens to quantify mRNA expression for 17 oncogenes and tumour suppressor genes. Three oncogenes, cell cycle regulator gene CDC5L, the RecQ DNA helicase gene RECQL4, and the cyclin-dependent kinase gene CDK4, were more highly expressed (p<0.05) in tumours which responded poorly to neoadjuvant chemotherapy. A similar trend (p<0.10) was identified for the osteoblast-specific transcription factor gene RUNX2. No statistically significant difference existed in comparing expression of CDC5L, RECQL4, CDK4, and RUNX2 between biopsy and resection samples. Additionally, analysis of expression data in the context of histological subtype yielded preliminary results for deducing molecular subtypes of osteosarcomas. Osteoblastic osteosarcomas possessed higher expression of CDKN1A, PTEN, and RUNX2 relative to their fibroblastic counterparts (p<0.05). This research study shows that CDC5L, RECQL4, and CDK4 tumour expression levels may be useful for identifying patients who may not benefit from the current standardized chemotherapy regimen. Total RNA was isolated from 52 pediatric osteosarcoma samples (prechemotherapy biopsies and resections), 3 osteosarcoma cell lines, and normal human osteoblasts. nanoString mRNA expression analysis was applied to samples split between 3 batches to compare samples based on clinical and pathologic data reports, and to compare samples with normal human osteoblasts. For 43 samples, there were complete data and the RNA was successfully assayed. Analysis was performed using R.
2016-03-15 | E-GEOD-45275 | biostudies-arrayexpress
Project description:RECQL4 depletion in human glioma cells with genetic tools slightly impaired cell viability and DNA replication, induced changes in gene expression and increased sensitivity of glioma cells and glioma stem cells to chemotherapeutics
2024-12-26 | GSE285044 | GEO
Project description:we generate iPSCs from a common fibroblast cell source using either the Yamanaka factors (OCT4, SOX2, KLF4 and MYC) or the Thomson factors (OCT4, SOX2, NANOG and LIN28) and determined their genome-wide DNA methylation profiles. In addition to shared DNA methylation aberrations present in all our iPSCs, we identify Yamanaka-iPSC (Y-iPSCs)-specific and Thomson-iPSCs (T-iPSC)-specific recurrent aberrations.
2014-01-16 | GSE54115 | GEO
Project description:Osteosarcoma is the most common malignancy of bone, and occurs most frequently in children and adolescents. Currently, the most reliable technique for prognostication is measuring histopathologic tumor necrosis following preoperative chemotherapy, and favourable prognosis is signified by 90% or greater estimated necrosis of the tumour. Neither genetic testing nor molecular biomarkers have been described for this tumour. We used the novel nanoString mRNA expression analysis system to analyzed total RNA from 35 flash-frozen sporadic paediatric osteosarcoma biopsy and resection specimens to quantify mRNA expression for 17 oncogenes and tumour suppressor genes. Three oncogenes, cell cycle regulator gene CDC5L, the RecQ DNA helicase gene RECQL4, and the cyclin-dependent kinase gene CDK4, were more highly expressed (p<0.05) in tumours which responded poorly to neoadjuvant chemotherapy. A similar trend (p<0.10) was identified for the osteoblast-specific transcription factor gene RUNX2. No statistically significant difference existed in comparing expression of CDC5L, RECQL4, CDK4, and RUNX2 between biopsy and resection samples. Additionally, analysis of expression data in the context of histological subtype yielded preliminary results for deducing molecular subtypes of osteosarcomas. Osteoblastic osteosarcomas possessed higher expression of CDKN1A, PTEN, and RUNX2 relative to their fibroblastic counterparts (p<0.05). This research study shows that CDC5L, RECQL4, and CDK4 tumour expression levels may be useful for identifying patients who may not benefit from the current standardized chemotherapy regimen.
2016-03-15 | GSE45275 | GEO
Project description:High-fat and high-sucrose diet impairs female reproduction by altering ovarian transcriptomic and metabolic signatures
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Project description:Deficiency of lncRNA SNHG12 impairs neovascularization in ischemic limbs by altering an endothelial cell cycle pathway III
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