Maintainability is as much an issue with DNA as it is, for example, with automobiles, which often have crucial components in hard-to-reach places. When DNA’s repair machinery tries to get “under the hood,” it sometimes has trouble getting to promoter regions, which tend to have more than their share of mutations.
In hopes of improving the DNA owner's manual—and helping to keep DNA roadworthy—two teams of scientists have focused on DNA promoter regions. Both teams have found that DNA repair machinery can be obstructed by DNA transcription machinery, which tends to engage promoter regions in order to initiate gene expression.
Both teams, one based at the University of New South Wales (UNSW) and one based at the Universitat Pompeu Fabra, published their findings April 13 in Nature. The UNSW team contributed an article entitled, “Differential DNA Repair Underlies Mutation Hotspots at Active Promoters in Cancer Genomes.” The Pompeu Fabra team contributed an article entitled, “Nucleotide Excision Repair Is Impaired by Binding of Transcription Factors to DNA.”
When the UNSW team analyzed more than 20 million DNA mutations from 1161 tumors across 14 cancer types, they found that in many cancer types, especially skin cancers, the number of mutations was particular high in gene promoter regions. Significantly, these DNA sequences control how genes are expressed, which in turn determines cell type and function.
The researchers showed that the numbers of DNA mutations are increased in gene promoters because the proteins that bind DNA to control gene expression block one of our cell repair systems responsible for fixing damaged DNA. This system is known as nucleotide excision repair (NER) and is one of a number of DNA repair mechanisms that occurs in human cells and the only one capable of repairing damage from ultraviolet (UV) light.
“Notably, analysis of genome-wide maps of NER shows that NER is impaired within the DHS centre of active gene promoters, while XPC-deficient skin cancers do not show increased promoter mutation density, pinpointing differential NER as the underlying cause of these mutation hotspots,” the UNSW-based contributors wrote. “Consistent with this finding, we observe that melanomas with an ultraviolet-induced DNA damage mutation signature show greatest enrichment of promoter mutations, whereas cancers that are not highly dependent on NER, such as colon cancer, show no sign of such enrichment.”
Lead author of the study Jason Wong, Ph.D., group leader of Bioinformatics and Integrative Genomics at UNSW's Lowy Cancer Research Centre, commented as follows: “What this research also tells us is that while the human body is pretty good at repairing itself, there are certain parts of our genome that are poorly repaired when we sustain damage from mutagens such as UV light and cigarette smoke. By actively avoiding these harmful environmental factors, we can minimize the number of mutations occurring in our body that can lead to cancer.”
Complementary results were obtained by the Pompeu Fabra team, which also suggested that inaccessible mutations have implications for our understanding of DNA repair processes and in the identification of cancer driver mutations.
“Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity,” the Pompeu Fabra-led contributors wrote. “Our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of DNA mutations at the protein binding sites.”