NEW YORK (GenomeWeb) – Two separate studies published online today in Nature are highlighting the role that DNA repair processes play in the production of mutation-prone sequences involved in cancer.
In one study, Australian researchers analyzed mutation densities at promoter, enhancer, gene coding, and heterochromatic sequences in nearly 1,200 whole-genome sequences for tumor samples from more than a dozen cancer types, with help from related cell type-specific data.
In several cancer types, the team detected higher-than-usual somatic mutation rates in promoter sequences sensitive to the DNase I enzyme — a marker for nucleosome-free sequences with transcription factor binding. When they put these data alongside nucleotide excision repair (NER) maps of the genome, the researchers saw clues that such mutations might stem from diminished NER activity at active promoter sites where transcription initiation typically occurs.
This pattern was especially prominent in cancer types containing mutation signatures related to NER activity, such as the ultraviolet light-linked mutations in melanoma or smoking-induced mutations in lung cancer. But it was missing in a form of skin cancer in patients with xeroderma pigmentosum, a condition characterized by germline mutations that inactivate components of the NER system, and in colon cancers stemming from mutations not normally repaired by NER.
"Taken together, our analysis has uncovered the presence of a previously unknown mechanism linking transcription initiation and NER as a major contributor of somatic point mutation hotspots at active gene promoters in cancer genomes," senior author Jason Wong, a researcher with the Prince of Wales Clinical School and Lowy Cancer Research Centre, and his co-authors wrote.
In the second study published today, a team from Spain wrote that it saw similar patterns when it scrutinized available genome sequences for more than three-dozen primary melanoma samples from The Cancer Genome Atlas project to look at the prevalence of somatic mutation rates at transcription factor binding sites.
In both tumor and normal skin samples, somatic mutations appeared to be enriched in active transcription factor binding sites compared to surrounding sequences. The researchers saw a similar jump in mutations in stretches of DNA wrapped around nucleosomes.
Their subsequent analyses, which tapped into available excision-repair sequencing data on UV irradiated skin fibroblast samples, pointed to decreased DNA repair by the NER at transcription factor binding sites, again suggesting that the system may have problems effectively accessing DNA bound by transcription factors or other proteins.
When the researchers looked at lung adenocarcinoma and lung squamous cell carcinomas, they found a similar somatic mutation rate rise across transcription factor binding sites, involving smoking-related mutation signatures that would normally be subject to NER.
"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," senior author Núria López-Bigas, a researcher affiliated with the Hospital del Mar, Pompeu Fabra University, and the Catalan Institution for Research and Advanced Studies, and her co-authors wrote.