Abstract
Because of imperfect discrimination against ribonucleoside triphosphates by the replicative DNA polymerases, large numbers of ribonucleotides are incorporated into the eukaryotic nuclear genome during S-phase. 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. Whereas 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-Goutieres syndrome. Here, we demonstrate that selective inactivation of RER in mouse epidermis results in spontaneous DNA damage and epidermal hyperproliferation associated with loss of hair follicle stem cells and hair follicle function. The animals developed keratinocyte intraepithelial neoplasia and invasive squamous cell carcinoma with complete penetrance, despite potent type I interferon production and skin inflammation. These results suggest that compromises to RER-mediated genome maintenance might represent an important tumor-promoting principle in human cancer. Significance: Selective inactivation of ribonucleotide excision repair by loss of RNase H2 in the murine epidermis results in spontaneous DNA damage, type I interferon response, skin inflammation, and development of squamous cell carcinoma.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Chemie und Pharmazie > Department Biochemie |
| Themengebiete: | 500 Naturwissenschaften und Mathematik > 540 Chemie |
| ISSN: | 0008-5472 |
| Sprache: | Englisch |
| Dokumenten ID: | 67196 |
| Datum der Veröffentlichung auf Open Access LMU: | 19. Jul. 2019, 12:22 |
| Letzte Änderungen: | 04. Nov. 2020, 13:49 |
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