Ribonucleotide excision repair prevents intestinal tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA436583 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6796070_1.fastq.gz | Fastqsanger.gz | |||
| SRR6796070_2.fastq.gz | Fastqsanger.gz | |||
| SRR6796080.fastq.gz | Fastqsanger.gz | |||
| SRR6796090.fastq.gz | Fastqsanger.gz | |||
| SRR6796071_1.fastq.gz | Fastqsanger.gz |
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Project description:Insufficient repair of DNA lesions results in the acquisition of somatic mutations and displays the driving force in cancerogenesis. Ribonucleotide incorporation by eukaryotic DNA polymerases occurs during every round of genome duplication and represents by far the most frequent type of naturally occurring DNA lesions. RNAse H2 removes misincorporated ribonucleotides from genomic DNA in a process termed ribonucleotide excision repair (RER). Whether intestinal epithelial proliferation requires RER and whether abrogation of RER is involved in the etiology of cancerogenesis at all is unknown. Mice with an epithelial specific deletion of RNase H2 subunit b (H2bΔIEC) and co-deletion of the tumor suppressor p53 (H2b/p53ΔIEC) were generated and phenotyped at young and old age. RNA sequencing was performed in isolated epithelial cells and intestinal organoids. Mutational signature of spontaneous tumors from H2b/p53ΔIEC mice were characterized using exome sequencing. Association of tumor RNase H2 expression and patient survival was assessed in transcriptome data from 467 CRC patients. H2bΔIEC mice display chronic epithelial DNA damage and develop a p53-dependent proliferative exhaustion of the intestinal stem cell compartment. H2b/p53ΔIEC mice have restored epithelial proliferation and spontaneously develop small intestinal carcinomas. Resulting tumors display a distinct mutational signature characterized by T>G base substitutions at GpTpG trinucleotides. Transcriptome data from human colorectal cancer patients indicate that reduced RNase H2 expression is associated with poor survival in CRC. Conclusion: We propose a hitherto unappreciated role for RNase H2 as a tumor suppressor gene in CRC. Our mouse model provides a novel tool to study the impact of abrogated RER on intestinal carcinogenesis.
2018-10-01 | GSE111318 | GEO
Project description:Ribonucleotide excision repair is essential to prevent skin cancer
| PRJNA473504 | ENA
Project description:Large numbers of ribonucleotides are incorporated into the eukaryotic nuclear genome during S-phase due to imperfect discrimination against ribonucleoside triphosphates by the replicative DNA polymerases. Ribonucleotides, by far the most common DNA lesion in replicating cells, destabilize the DNA, and an evolutionarily conserved DNA repair machinery, ribonucleotide excision repair (RER), ensures ribonucleotide removal. Complete lack of RER is embryonically lethal. Partial loss-of-function mutations in the genes encoding subunits of RNase H2, the enzyme essential for initiation of RER, cause the SLE-related type I interferonopathy Aicardi-Goutières syndrome. Here we establish that selective inactivation of RER in mouse epidermis results in spontaneous DNA damage, epidermal hyperproliferation associated with loss of hair follicle stem cells and hair follicle function. The animals develop keratinocyte intraepithelial neoplasia and invasive squamous cell carcinoma with complete penetrance, despite potent type I interferon production and skin inflammation. Compromised RER-mediated genome maintenance might represent an important tumor-promoting principle in human cancer.
2019-05-29 | GSE115003 | GEO
Project description:Large numbers of ribonucleotides are incorporated into the eukaryotic nuclear genome during S-phase due to imperfect discrimination against ribonucleoside triphosphates by the replicative DNA polymerases. Ribonucleotides, by far the most common DNA lesion in replicating cells, destabilize the DNA, and an evolutionarily conserved DNA repair machinery, ribonucleotide excision repair (RER), ensures ribonucleotide removal. Complete lack of RER is embryonically lethal. Partial loss-of-function mutations in the genes encoding subunits of RNase H2, the enzyme essential for initiation of RER, cause the SLE-related type I interferonopathy Aicardi-Goutières syndrome. Here we establish that selective inactivation of RER in mouse epidermis results in spontaneous DNA damage, epidermal hyperproliferation associated with loss of hair follicle stem cells and hair follicle function. The animals develop keratinocyte intraepithelial neoplasia and invasive squamous cell carcinoma with complete penetrance, despite potent type I interferon production and skin inflammation. Compromised RER-mediated genome maintenance might represent an important tumor-promoting principle in human cancer.
2019-05-29 | GSE115004 | GEO
Project description:Ribonucleotide excision repair is essential to prevent skin cancer [CD49f+ epidermal cells]
| PRJNA473507 | ENA
Project description:Ribonucleotide excision repair is essential to prevent skin cancer [CD45+ CD49f- epidermal cells]
| PRJNA473510 | ENA
Project description:We report the application of single-molecule-based sequencing technology (XR-seq) for high-throughput profiling of nucleotide excision repair in Drosophila four developmental stages and S2 cells. By obtaining over six billion bases of sequence from UV and cisplatin damage antibodies immunoprecipitated excision DNA, we generated genome-wide nucleotide excision repair maps of Drosophila Embryo, Larva, Pupa , two gender of adults and S2 cells . We find that Drosophila performs transcription-coupled repair (TCR) at all its developmental stages. S2 cell carry out TCR response to both UV and Cisplatin damage. Finally, we show that XPC repair factor is required for both global and transcription-coupled repair in Drosophila. This study provides the mechanism of nucleotide excision repair of Drosophila in vivo and vitro response to UV and Cisplatin damage.
2022-02-25 | GSE184926 | GEO
Project description:Transcriptional analysis of nucleotide excision repair defects
| PRJNA714383 | ENA
Project description:Ribonucleotides incorporated in the genome are a source of endogenous DNA damage, and also serve as signals for repair. Although recent advances of ribonucleotide detection by sequencing, the balance between incorporation and repair of ribonucleotides has not been elucidated. Here, we describe a competitive sequencing method, Ribonucleotide Scanning Quantification sequencing (RiSQ-seq), which enables absolute quantification of misincorporated ribonucleotides throughout the genome by background normalization and standard adjustment within a single sample. RiSQ-seq analysis of cells harboring wild-type DNA polymerases revealed that ribonucleotides were incorporated non-uniformly in the genome with a 3’-shifted distribution and preference for GC sequences. Although ribonucleotide profiles in wild-type and repair-deficient mutant strains showed a similar pattern, direct comparison of distinct ribonucleotide levels in the strains by RiSQ-seq enabled evaluation of ribonucleotide excision repair activity at base resolution and revealed the strand bias of repair. The distinct preferences of ribonucleotide incorporation and repair create vulnerable regions associated with indel hotspots, suggesting that repair at sites of ribonucleotide misincorporation serves to maintain genome integrity and that RiSQ-seq can provide an estimate of indel risk.
2021-05-21 | GSE85130 | GEO