Published in Nature: By simply analysing existing and publicly available ‘big data’, UNSW medical scientists have discovered that a DNA repair mechanism that protects our cells from becoming cancerous is compromised at important regions of our genome.
The researchers analysed more than 20 million DNA mutations from 1,161 tumours across 14 cancer types. They found that in many cancer types, especially skin cancers, the number of mutations is particular high in regions of the genome known as ‘gene promoters’. These DNA sequences control how genes are expressed which in turn determine cell type and function.
The research findings indicate that the observed hotspots of mutations at gene promoter sites are a result of a less efficient repair of the DNA by the nucleotide excision repair (NER) system.
The evidence for this includes the finding that certain cancers in which NER plays a key role, such as melanoma and smoking-related lung cancer, also show a higher promoter mutation density.
NER is one of a number of DNA repair mechanisms in human cells but the only one capable of repairing damage from UV light.As potential reason for the NER impairment the researchers implicate so called transcription factors. These are proteins that bind to DNA within active gene promoter sites to control gene expression. However, they may also interfer with the NER, which from an evolutionary perspective is an intriguing finding, the researchers say:
It suggests that the mechanism that controls protein expression may also permit a higher density of potentially cancer promoting mutations at gene promoter sites.
Internationally, scientists have so far identified only one promoter mutation, known as the telomerase reverse transcriptase (TERT) gene, that definitively contributes to cancer.
According to project leader Dr Jason Wong, further research is therefore needed on the role of gene promoter mutations in cancer development.