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Series GSE111318 Query DataSets for GSE111318
Status Public on Oct 01, 2018
Title Ribonucleotide excision repair prevents intestinal tumorigenesis
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design RNA sequencing of i) isolated epithelial crypts from aged H2Bfl/fl and H2BdIEC mice, ii) intestinal organoids from H2Bfl/fl, H2BdIEC and H2B/p53dIEC and iii) tumor tissue and surrounding unaffected tissue of H2B/p53dIEC and H2B/p53fl/fl
Contributor(s) Konrad A, Rosenstiel P
Citation(s) 30273559
Submission date Mar 01, 2018
Last update date Feb 11, 2019
Contact name Neha Mishra
Organization name Institute of Clinical Molecular Biology
Lab Cell biology Lab
Street address Rosalind-Franklin-Str. 12
City Kiel
ZIP/Postal code 24105
Country Germany
Platforms (1)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
Samples (29)
GSM3028404 KA_182_SI_Crypt_970
GSM3028405 KA_182_SI_Crypt_971
GSM3028406 KA_182_SI_Crypt_972
BioProject PRJNA436583
SRA SRP133781

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Supplementary file Size Download File type/resource
GSE111318_RAW.tar 5.1 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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