Novel insights into bulky DNA damage formation and nucleotide excision repair from high-resolution genomics.

DNA damages compromise cell function and fate. Cells of all organisms activate a global DNA damage response that includes a signaling stress response, activation of checkpoints, and recruitment of repair enzymes. Especially deleterious are bulky, helix-distorting damages that block transcription and replication. Due to their miscoding nature, these damages lead to mutations and cancer. In human cells, bulky DNA damages are repaired by nucleotide excision repair (NER). To date, the basic mechanism of NER in naked DNA is well defined. Still, there is a fundamental gap in our understanding of how repair is orchestrated despite the packaging of DNA in chromatin, and how it is coordinated with active transcription and replication. The last decade has brought forth huge advances in our ability to detect and assay bulky DNA damages and their repair at single nucleotide resolution across the human genome. Here we review recent findings on the effect of chromatin and DNA-binding proteins on the formation of bulky DNA damages, and novel insights on NER, provided by the recent application of genomic methods.