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Down-regulation of cholesterol biosynthesis in forebrains of ERCC1-deficient mice

ABSTRACT: Background: Several genetic defects of the nucleotide excision repair (NER) pathway, including deficiency of the Excision Repair Cross-Complementing rodent repair deficiency, complementation group 1 (ERCC1), result in pre-mature aging, impaired growth, microcephaly and delayed development of the cerebellum. Such a phenotype also occurs in ERCC1-knockout mice which survive for up to 4 weeks after birth. Therefore, we analyzed cerebellar and hippocamapal transcriptomes of these animals at 3 weeks of age to identify the candidate mechanisms underlying brain consequences of reduced ERCC1 activity. Results: In the cerebellum, the most prominent change was upregulation of genes that are associated with gliosis. Although Purkinje cell degeneration has been reported in some mouse strains with NER impairment, Purkinje cell transcriptome was mostly unaffected by the ERCC1 knockout. In the hippocampus, the gliosis response was minimal. Instead, there was an extensive downregulation of genes related to lipid metabolism including several enzymes of the cholesterol biosynthesis pathway as well as lipoproteins and plasma membrane proteins. Reduced expression of the cholesterol biosynthesis pathway genes was also present in the neocortex of adult mice whose ERCC1 gene was replaced by a mutant allele with a partial activity. Conclusions: Downregulation of forebrain cholesterol biosynthesis genes is a newly identified consequence of ERCC1 deficiency. Its presence in adult mice suggests that it is not a secondary consequence of brain growth impairment. Instead, reduced cholesterol biosynthesis may contribute to such an impairment as well as affect function of mature synapses.

ORGANISM(S): Mus musculus

PROVIDER: GSE31199 | GEO | 2011/08/16

SECONDARY ACCESSION(S): PRJNA144745

REPOSITORIES: GEO

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Down-regulation of cholesterol biosynthesis in forebrains of ERCC1-deficient mice

Project description:Background: Several genetic defects of the nucleotide excision repair (NER) pathway, including deficiency of the Excision Repair Cross-Complementing rodent repair deficiency, complementation group 1 (ERCC1), result in pre-mature aging, impaired growth, microcephaly and delayed development of the cerebellum. Such a phenotype also occurs in ERCC1-knockout mice which survive for up to 4 weeks after birth. Therefore, we analyzed cerebellar and hippocamapal transcriptomes of these animals at 3 weeks of age to identify the candidate mechanisms underlying brain consequences of reduced ERCC1 activity. Results: In the cerebellum, the most prominent change was upregulation of genes that are associated with gliosis. Although Purkinje cell degeneration has been reported in some mouse strains with NER impairment, Purkinje cell transcriptome was mostly unaffected by the ERCC1 knockout. In the hippocampus, the gliosis response was minimal. Instead, there was an extensive downregulation of genes related to lipid metabolism including several enzymes of the cholesterol biosynthesis pathway as well as lipoproteins and plasma membrane proteins. Reduced expression of the cholesterol biosynthesis pathway genes was also present in the neocortex of adult mice whose ERCC1 gene was replaced by a mutant allele with a partial activity. Conclusions: Downregulation of forebrain cholesterol biosynthesis genes is a newly identified consequence of ERCC1 deficiency. Its presence in adult mice suggests that it is not a secondary consequence of brain growth impairment. Instead, reduced cholesterol biosynthesis may contribute to such an impairment as well as affect function of mature synapses. We analyzed the hippocampus and cerebellum from three Ercc1-/- and three WT littermates using the Affymetrix Mouse Genome 430_2.0. Data was analyzed using the dChip DNA-Chip analyzer software .

2011-08-15 | E-GEOD-31199 | biostudies-arrayexpress

Two siblings with strong NER inactivation due to inherited ERCC1 deficiency display mild clinical features of XP and CS with severe liver impairment

Project description:The ERCC1-XPF heterodimer is a multifunctional endonuclease involved in nucleotide excision repair (NER), inter-strand crosslink (ICL) repair, and DNA double-strand break (DSB) repair. Only two patients with inherited ERCC1 defects have been reported who both died at an early age. Here, we describe a new case of ERCC1 deficiency in two siblings (11 and 13 years) who show mild features of Xeroderma Pigmentosum and Cockayne Syndrome. Both patients displayed microcephaly, mild developmental delay, mild photosensitivity, and severe cholestatic liver problems. Genetic analysis revealed a maternal deletion and a paternal missense variant in ERCC1 (R156W) that affect a salt bridge just below the XPA-binding pocket. Studies in patient-derived fibroblasts and reconstituted knockout cells confirmed that mutant ERCC1 is not efficiently recruited to the NER complex due to a decreased interaction with XPA. Consequently, patient cells show a strong NER defect, although residual repair could be detected. The steady-state protein levels of ERCC1 and XPF were severely reduced in patient cells, but this only led to a mild defect in ICL repair, and no impact on DSB repair. We report a new case of ERCC1 deficiency that particularly affect NER and has only a mild impact on other ERCC1-dependent repair pathways.

2021-01-26 | PXD017940 | Pride

Identify the protein partners of Ercc1 in DNA damage progeria in MEFs

Project description:ERCC1 is a DNA endonuclease participating in the Nucleotide Excision Repair (NER) pathway. Its functionality is related to XPF; the two proteins work as a heterodimer to incise the 5 of a 30-mer that contains the damaged nucleotide and remove the fragment together with XPG. Apart from NER deficiency, mutated Ercc1 in mice and humans causes a series of progeroid symptoms (premature ageing). We hypothesize that there are undescribed functions of ERCC1, possibly in transcriptional regulation that contribute to the development of the striking phenotypes observed. The aim is to identify previously uncharacterized protein partners of ERCC1 that might contribute to our understanding of its differential roles during DNA damage-driven progeria.

2023-10-04 | PXD017063 | Pride

A disease-associated XPA allele interferes with TFIIH binding and primarily affects the transcription-coupled sub-pathway of nucleotide excision repair

Project description:XPA is a central scaffold protein in nucleotide excision repair (NER) that interacts with and coordinates the assembly of repair complexes. Inactivating mutations in XPA causes Xeroderma Pigmentosum (XP), which is characterized by extreme UV sensitivity and a highly elevated skin cancer risk. Here, we describe two Dutch siblings in their late forties carrying a homozygous H244R substitution in the C-terminus of XPA with a mild manifestation of XP without skin cancer, but with neurological features including cerebellar ataxia. We show that the mutant XPA protein shows a severely weakened interaction with the TFIIH complex leading to its inefficient association with NER complexes and an inability to support the efficient association of the ERCC1-XPF endonuclease with repair complexes. Despite these defects, we find that patient-derived fibroblasts and reconstituted knockout cells carrying the H244R substitution show considerable levels of residual global genome repair (~40%), which is in intrinsic property of the mutated protein as revealed by in vitro experiments. In contrast, patient fibroblasts and engineered cells only expressing the mutant XPA protein were fully deficient in transcription-coupled repair. We report a new case of XPA deficiency that interferes with TFIIH binding and primarily affects the transcription-coupled sub-pathway of nucleotide excision repair, which is more closely associated with neurological features than to skin abnormalities.

2023-02-19 | PXD033520 | Pride

MiR-192 inhibits nucleotide excision repair by targeting ERCC3 and ERCC4 in HepG2.2.15 cells.

Project description:Deficient DNA repair capacity is associated with genetic lesions accumulation and susceptibility to carcinogenesis. MicroRNAs (miRNAs) are small non-coding RNAs that regulate various cellular pathways including DNA repair. Here we hypothesized that the existence of HBV products may interfere with cellular nucleotide excision repair (NER) through microRNA-mediated gene regulation. We found that NER was impaired in HepG2.2.15 cells, a stable HBV-expressing cell line, compared with its parental cell line HepG2. Altered miRNA expression profile, in particular the significant upregulation of miR-192, was observed in HepG2.2.15 cells. Additionally, ERCC3 and ERCC4, two key factors implicated in NER, were identified as targets of miR-192 and over-expressing miR-192 significantly inhibited cellular NER. These results indicated that persistent HBV infection might trigger NER impairment in part through upregulation of miR-192, which suppressed the levels of ERCC3 and ERCC4. It provides new insight into the effect of chronic HBV infection on NER and genetic instability in cancer. A genome-wide miRNAs microarray was performed to identify differentially expressed miRNAs between HepG2.2.15, a stable HBV-expressing cell line, and its parental cell line HepG2.

2011-08-02 | E-GEOD-27561 | biostudies-arrayexpress

ERCC1-XPF Cooperates with CTCF and the Cohesin to Facilitate the Developmental Silencing of Imprinted Genes

Project description:Inborn defects in DNA repairare associated with complex developmental disorders whose causal mechanisms are poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the nucleotide excision repair (NER) structure-specific endonuclease ERCC1-XPF complex interacts with the insulator binding protein CTCF, the cohesin subunits SMC1A and SMC3 and with MBD2; the factors co-localize with ATRX at the promoters and control regions (ICRs) of imprinted genes during postnatal hepatic development. Loss of Ercc1or exposure to mitomycin C triggers the localization of CTCF to heterochromatin, the dissociation of the CTCF-cohesin complex and ATRXfrom promoters and ICRs,altered histone marks and the aberrant developmental expression of imprinted genes without altering DNA methylation. We propose that ERCC1-XPF cooperates with CTCF and the cohesinto facilitatet he developmental silencing of imprinted genes and that persistent DNA damage triggers chromatin changes that affect gene expression programs associated with NER disorders.

2017-04-04 | PXD005897 | Pride

MiR-192 inhibits nucleotide excision repair by targeting ERCC3 and ERCC4 in HepG2.2.15 cells.

2011-08-03 | GSE27561 | GEO

Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting

Project description:Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in cancer. HR-deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of HR deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Using whole exome and genome sequencing data, we found that a significant subset of GEA, but very few colorectal adenocarcinomas, show evidence of HR deficiency by mutational signature analysis (HRD score). High HRD gastric cancer cell lines demonstrated functional HR deficiency by RAD51 foci assay and increased sensitivity to platinum chemotherapy and PARP inhibitors. Of clinical relevance, analysis of three different GEA patient cohorts demonstrated that platinum treated HR deficient cancers had better outcomes. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by two photoproduct repair assays. Single-cell RNA-sequencing revealed that, in addition to inducing apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, validated by intracellular GSH assay. Overall, our study provides preclinical evidence that a subset of GEAs harbor genomic features of HR and NER deficiency and may therefore benefit from platinum chemotherapy and PARP inhibitors.

2024-02-23 | GSE256301 | GEO

Genome-wide mutational consequences of nucleotide excision repair-deficiency through XPC deletion in a human adult stem cell culture

Project description:Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Deficiency in this pathway can contribute to the development of cancer and accelerate aging. NER-deficiency is an important determinant for cancer treatment outcome, as NER-deficient tumors are selectively sensitive to cisplatin treatment. While NER-deficiency has been linked to mutational Signature 5, not all NER-deficient tumors are characterized by a high Signature 5 contribution, illustrating the importance to further characterize the mutational consequences of NER-deficiency. Here, we analyzed the mutational profile of a human adult stem cell (organoid) culture that is deficient in NER through XPC deletion by CRISPR-Cas9 gene-editing, and subsequent whole-genome sequencing analysis of a clonally derived organoid. We found that XPC deletion results in an increase in base substitution load and specifically induces Signature 8 mutations, a mutational signature with previously unknown etiology. Presence of Signature 8 may, therefore, serve as a novel biomarker for NER-deficient tumors and could improve personalized treatment strategies.

| EGAS00001002681 | EGA

Global Genome-Nucleotide Excision Repair is Organised into Domains Promoting Efficient DNA Repair in Chromatin

Project description:The rates at which lesions are removed by DNA repair can vary widely throughout the genome with important implications for genomic stability. We measured the distribution of nucleotide excision repair (NER) rates for UV induced lesions throughout the yeast genome. By plotting these repair rates in relation to all ORFs and their associated flanking sequences, we reveal that in normal cells, genomic repair rates display a distinctive pattern, suggesting that DNA repair is highly organised within the genome. We compared genome-wide DNA repair rates in wild type and in RAD16 deleted cells, which are defective in the global genome-NER (GG-NER) sub-pathway, demonstrating how this alters the normalâ¨distribution of NER rates throughout the genome. We examine the genomic locations of global genome NER factor binding in chromatin before and after UV irradiation, and reveal that GG-NER is organized and initiated from specific locations. By controlling the chromatin occupancy of the histone acetyl transferase Gcn5, the GG-NER complex regulates the histone H3 acetylation status and chromatin structure in the vicinity of these genomic sites to promote the efficient DNA repair of UV induced lesions. This demonstrates that chromatin remodeling during the GG-NER process is organized into domains in the genome. Importantly, we demonstrate that deleting the histone modifier GCN5, an accessory factor required for chromatin remodeling during GG-NER, significantly alters the genomic distribution of NER rates. These observations could have important implications for the effect of histone and chromatin modifiers on the distribution of genomic mutations acquired throughout the genome.

2016-07-21 | E-MTAB-4641 | biostudies-arrayexpress

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