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| Status |
Public on Oct 01, 2018 |
| Title |
Ribonucleotide excision repair prevents intestinal tumorigenesis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| 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.
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| 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
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| Contributor(s) |
Konrad A, Rosenstiel P |
| Citation(s) |
30273559 |
| Submission date |
Mar 01, 2018 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Neha Mishra |
| E-mail(s) |
n.mishra@ikmb.uni-kiel.de
|
| 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 |
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| Platforms (1) |
| GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
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| Samples (29)
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| Relations |
| BioProject |
PRJNA436583 |
| SRA |
SRP133781 |
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