1. Cancer Biology
Download icon

Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

  1. Blake Ferguson
  2. Herlina Y Handoko
  3. Pamela Mukhopadhyay
  4. Arash Chitsazan
  5. Lois Balmer
  6. Grant Morahan
  7. Graeme J Walker  Is a corresponding author
  1. QIMR Berghofer Medical Research Institute, Australia
  2. Harry Perkins Institute of Medical Research, Australia
Research Article
  • Cited 10
  • Views 1,322
  • Annotations
Cite this article as: eLife 2019;8:e42424 doi: 10.7554/eLife.42424

Abstract

Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this 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.

Data availability

All data generated in this manuscript are provided in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. Blake Ferguson

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Herlina Y Handoko

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Pamela Mukhopadhyay

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Arash Chitsazan

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Lois Balmer

    Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Grant Morahan

    Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Graeme J Walker

    QIMR Berghofer Medical Research Institute, Herston, Australia
    For correspondence
    Graeme.Walker@qimr.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9392-8769

Funding

Melanoma Research Alliance (Investigator Grant Award Number: 346859 2015-2018)

  • Graeme J Walker

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations Australian code of Practice for the care and use of animals for scientific purposes.. All of the animals were handled according to approved institutional animal care and use committee of the Queensland Institute of Medical research. The protocol was approved by the Committee (A98004M). No surgery was performed. Animals were sacrificed when tumours reached 10mm in diameter, or animals were otherwise distressed.

Reviewing Editor

  1. Richard M White, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: October 2, 2018
  2. Accepted: January 25, 2019
  3. Accepted Manuscript published: January 25, 2019 (version 1)
  4. Version of Record published: March 21, 2019 (version 2)

Copyright

© 2019, Ferguson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,322
    Page views
  • 235
    Downloads
  • 10
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Cell Biology
    Maxim I Maron et al.
    Research Article Updated

    Protein arginine methyltransferases (PRMTs) are required for the regulation of RNA processing factors. Type I PRMT enzymes catalyze mono- and asymmetric dimethylation; Type II enzymes catalyze mono- and symmetric dimethylation. To understand the specific mechanisms of PRMT activity in splicing regulation, we inhibited Type I and II PRMTs and probed their transcriptomic consequences. Using the newly developed Splicing Kinetics and Transcript Elongation Rates by Sequencing (SKaTER-seq) method, analysis of co-transcriptional splicing demonstrated that PRMT inhibition resulted in altered splicing rates. Surprisingly, co-transcriptional splicing kinetics did not correlate with final changes in splicing of polyadenylated RNA. This was particularly true for retained introns (RI). By using actinomycin D to inhibit ongoing transcription, we determined that PRMTs post-transcriptionally regulate RI. Subsequent proteomic analysis of both PRMT-inhibited chromatin and chromatin-associated polyadenylated RNA identified altered binding of many proteins, including the Type I substrate, CHTOP, and the Type II substrate, SmB. Targeted mutagenesis of all methylarginine sites in SmD3, SmB, and SmD1 recapitulated splicing changes seen with Type II PRMT inhibition, without disrupting snRNP assembly. Similarly, mutagenesis of all methylarginine sites in CHTOP recapitulated the splicing changes seen with Type I PRMT inhibition. Examination of subcellular fractions further revealed that RI were enriched in the nucleoplasm and chromatin. Taken together, these data demonstrate that, through Sm and CHTOP arginine methylation, PRMTs regulate the post-transcriptional processing of nuclear, detained introns.

    1. Cancer Biology
    2. Ecology
    Daniel Garcia-Souto et al.
    Short Report

    Clonally transmissible cancers are tumour lineages that are transmitted between individuals via the transfer of living cancer cells. In marine bivalves, leukaemia-like transmissible cancers, called hemic neoplasia (HN), have demonstrated the ability to infect individuals from different species. We performed whole-genome sequencing in eight warty venus clams that were diagnosed with HN, from two sampling points located more than 1000 nautical miles away in the Atlantic Ocean and the Mediterranean Sea Coasts of Spain. Mitochondrial genome sequencing analysis from neoplastic animals revealed the coexistence of haplotypes from two different clam species. Phylogenies estimated from mitochondrial and nuclear markers confirmed this leukaemia originated in striped venus clams and later transmitted to clams of the species warty venus, in which it survives as a contagious cancer. The analysis of mitochondrial and nuclear gene sequences supports all studied tumours belong to a single neoplastic lineage that spreads in the Seas of Southern Europe.