Cancer genomics: Hard-to-reach repairs.

Abstract

Two studies find that the molecular machinery that initiates gene transcription prevents repair proteins from accessing DNA, resulting in increased mutation rates at sites of transcription-factor binding. See Letters p.259 & p.264 Recent whole-genome analyses in cancer have identified numerous hotspots of somatic point mutations within gene promoters. Two papers in this issue of Nature examine this relationship and find evidence for mechanisms linking transcription initiation and DNA repair. Jason Wong and colleagues analyse more than a thousand cancer genomes across 14 cancer types and find that increased mutation density at gene promoters is linked to transcription initiation activity and impairment of nucleotide excision repair. The density of promoter mutations can be correlated with the dependence of the cancer on excision repair. Nuria Lopez-Bigas and colleagues report an analysis of genomic data from melanomas, finding an increased rate of somatic mutations at active transcription factor binding sites within promoter regions. The increased mutation rate at these genomic regions can be explained by reduced accessibility of the protein-bound DNA to nucleotide excision repair.