Document Type
Journal Article
Publication Title
eLife
ISSN
2050-084X
Volume
8
PubMed ID
30681412
Publisher
eLife Sciences Publications, Ltd
School
School of Medical and Health Sciences
RAS ID
28150
Funders
Melanoma Research Alliance Investigator Grant Award Number: 346859 2015-2018 Graeme J Walker
Abstract
Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this idea to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to Prkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene Rrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure. Mechanistically, variation in the ‘usual suspects’ by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.
DOI
10.7554/eLife.42424
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Ferguson, B., Handoko, H. Y., Mukhopadhyay, P., Chitsazan, A., Balmer, L., Morahan, G., & Walker, G. J. (2019). Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma. eLife, 8, Article e42424. Available here