The onset of melanoma in Cdk4:Nras mice can be accelerated by modifier genes normally present in the genetic background of other mouse strains. Normal variants in Prkdc (green, top) made spontaneous melanomas appear faster. This gene codes for a protein that is well-known for repairing DNA strand breaks, and less well-known as an RNA binding protein that chemically modifies proteins involved in transcription, receptor signaling, and cytokine synthesis. Normal variants in Rrp15 (purple, bottom) made neonatal UV melanomas appear more quickly. This gene codes for an RNA-binding protein that is involved in cell cycle arrest, apoptosis, and cell migration and invasion. Because UV turns on the Rrp15 gene, this result highlights how the environment can lead to cancer by triggering large-scale physiological changes that precede, rather than follow, ‘driver’ mutations.