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Ribonucleotide excision repair is essential to prevent skin cancer [CD45+ CD49f- epidermal cells]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE115004 | GEO | 2019/05/29

REPOSITORIES: GEO

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Ribonucleotide excision repair is essential to prevent skin cancer [CD49f+ epidermal cells]

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

Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model [EmRibo-seq]

Project description:All DNA polymerases misincorporate ribonucleotides despite their preference for deoxyribonucleotides, and analysis of cultured cells indicates that mammalian mitochondrial DNA (mtDNA) tolerates such replication errors. However, it is not clear to what extent ribonucleotides are incorporated into the mtDNA of solid tissues, or whether they might play a role in human pathologies. Here, we show the DNA in mitochondria of solid tissues contains many more embedded ribonucleotides than that of cultured cells, consistent with the former’s high ratio of ribonucleotide to deoxynucleotide triphosphates and that rAMPs are the predominant ribosubstitution events. This pattern changes in a mouse model of Mpv17 deficiency, as rGMPs are the major embedded ribonucleotides of mtDNA. However, while mitochondrial dGTP is reduced in the liver of the KO mice, the brain shows no change in the overall dGTP pool, leading us to infer that Mpv17 determines the local concentration or quality of dGTP. Embedded rGMPs are expected to impede DNA replication more than other rNMPs, and elevated rGMP incorporation is associated with early-onset mtDNA depletion in liver and late-onset multiple deletions in brain of the Mpv17 ablated mice. These findings suggest that aberrant ribonucleotide incorporation is a primary mtDNA abnormality that can result in pathology.

2017-10-23 | GSE103429 | GEO

Ribonucleotides incorporated by the yeast mitochondrial DNA polymerase are not repaired

Project description:Misincorporation of ribonucleotides into DNA during genome replication has recently become recognized as a significant source of genomic instability. The frequency of ribonucleotides in the genome is determined by dNTP/rNTP ratios, the ability of the DNA polymerases to discriminate against ribonucleotides, and by the capacity of repair mechanisms to remove misincorporated ribonucleotides. To simultaneously compare how the nuclear and mitochondrial genomes incorporate and remove ribonucleotides, we challenged these processes by imbalancing cellular dNTP pools. Using a collection of yeast strains with altered dNTP pools, we discovered an inverse relationship between the concentration of individual dNTPs and the amount of the corresponding ribonucleotides incorporated in mitochondrial DNA, while in nuclear DNA the ribonucleotide pattern was only altered in the absence of ribonucleotide excision repair. Our analysis uncovers major differences in ribonucleotide repair between the two genomes and provides concrete evidence that yeast mitochondria lack mechanisms for repair of misincorporated ribonucleotides.

2017-11-07 | GSE100352 | GEO

Ribonucleotide excision repair prevents intestinal tumorigenesis

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

Evaluation of Repair Activity by Quantification of Ribonucleotides in the Genome

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

Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation

Project description:Multiple DNA polymerases are needed to replicate genetic information. Here we describe the use of ribonucleotide incorporation as a biomarker of replication enzymology in vivo. We find that ribonucleotides are incorporated into the yeast nuclear genome in replicase specific and strand-specific patterns that identify replication origins and where polymerase switching occurs. Ribonucleotide density varies across the genome as a function of the replicase, base, local sequence and proximity to nucleosomes and transcription start sites. Ribonucleotides are present in one strand at high densityat mitochondrial replication origins, implying unidirectional replication of a circular genome. The evolutionary conservation of the enzymes that incorporate and process ribonucleotides in DNA suggests that the use of ribonucleotides as biomarkers of DNA synthesis in cells will have widespread applicability. Mapping genomic ribonucleotides in 14 Saccharomyces cerevisiae strains (seven DNA polymerase backgrounds, with or without RNH201), via HydEn-seq (end sequencing of genomic fragments generated by alkaline hydrolysis).

2015-01-26 | E-GEOD-62181 | biostudies-arrayexpress

Stably incorporated ribonucleotides in murine tissues: quantitation, base identity and distribution in nuclear and mitochondrial DNA

Project description:Ribonucleotides are estimated to be the most common non-canonical nucleotides transiently incorporated in DNA. Their presence or failure of their removal can affect genome stability and mutations in factors involved in dNTP pool maintenance or ribonucleotide removal can cause Aicardi-Goutières syndrome or promote certain human cancers. Here, we have mapped and quantitated ribonucleotides genome-wide, in nine tissues of wild-type mice. We observed tissue-specific variation in number and base identity of incorporated ribonucleotides and present evidence that a number of genomic features, such as tRNA genes, transcription start sites and G-quadruplexes, can increase the frequency of stably incorporated ribonucleotides in their proximity. Moreover, we present the non-random distribution of incorporated ribonucleotides in mtDNA and identified ribonucleotide hotpots. The study presents a framework to understand the physiological role of ribonucleotides in mammalian DNA.

2024-09-01 | GSE183589 | GEO

Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation

2015-01-26 | GSE62181 | GEO

Recognition of DNA damage lesions across the tree of life

Project description:Protecting the integrity of their genome is critical to all species. The surveillance and maintenance of the genome of every organism is orchestrated by a highly regulated combination of DNA damage response and specific DNA repair pathways. Two of these critical pathways are base excision repair (BER) and ribonucleotide excision repair (RER). Here, we investigate the phylogenetic diversity in the recognition and repair of three well-established DNA lesions, primarily repaired by BER or RER: 1) 8-oxoguanine, 2) an abasic site, and 3) incorporated ribonucleotide in DNA in E. coli, B. subtilis, H. salinarum, T. brucei, T. thermophila, S. cerevisiae, S. pombe, C. elegans, human HeLa and HEK293 cells, A. thaliana, and Z. mays. Using quantitative mass spectrometry, we identified 337 enriched interactors across these species. Of these proteins, 140 were previously characterized to be involved in DNA repair, and 39 proteins were newly identified due to their homology to previously studied repair proteins. For 10 of the 11 species, we identify unique, uncharacterized proteins that lack homology to any protein within the included 11 species. Our study emphasizes strong crosstalk between RER and BER and highlights the evolutionary conservation of this cross recognition across all domains of life.

2023-07-20 | PXD036040 | Pride

Genome wide maps of replicative polymerase contributions to the fully replicated yeast genome

Project description:We report the application of high through-put tag sequencing to measure the location and strand of DNA embedded ribonucleotides in the yeast genome. Mutations in the catalytic subunits of the polymerases (pol1-L868M, pol2-M644G and pol3-L612M) lead to the increased incorporation of ribonucleotides during DNA replication, providing an in vivo label with which to track the contribution of each polymerase to the fully replicated genome. Yeast strains used in this study are deleted for rnh201, encoding the catalytic subunit of the RNase H2 gene so that embedded ribonucleotides are not rapidly removed by ribonucleotide excision repair following DNA replication. Analysis of this data demonstrates that polymerase alpha contributes to the fully replicated genome. Sequencing of DNA embedded ribonucleotides in S. cerevisiae strains to map the contribution of replicative polymerases to the fully replicated genome.

2015-01-26 | E-GEOD-64521 | biostudies-arrayexpress

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