The excision of mutagenic DNA adducts by the nucleotide excision repair (NER) pathway is essential for genome stability, which is key to avoiding genetic diseases, premature aging, cancer and neurologic disorders. Due to the need to process an extraordinarily high damage density embedded in the nucleosome landscape of chromatin, NER activity provides a unique functional caliper to understand how histone modifiers modulate DNA damage responses. At least three distinct lysine methyltransferases (KMTs) targeting histones have been shown to facilitate the detection of ultraviolet (UV) light-induced DNA lesions in the difficult to access DNA wrapped around histones in nucleosomes. By methylating core histones, these KMTs generate docking sites for DNA damage recognition factors before the chromatin structure is ultimately relaxed and the offending lesions are effectively excised. In view of their function in priming nucleosomes for DNA repair, mutations of genes coding for these KMTs are expected to cause the accumulation of DNA damage promoting cancer and other chronic diseases. Research on the question of how KMTs modulate DNA repair will, therefore, pave the way to the development of pharmacologic agents for new therapeutic strategies. Introduction Genome stability is constantly threatened by endogenous and exogenous DNA-damaging agents that induce a variety of DNA lesions. A network of DNA repair processes avoids the conversion of DNA damage to mutations and chromosomal aberrations, thus preventing genetic diseases, premature aging, cancer and other chronic conditions (1-3). Nucleotide excision repair (NER) is the DNA repair process dedicated to the removal of a broad spectrum of structurally unrelated DNA adducts that are typically larger than normal nucleotides. These "bulky" lesions arise at high frequency and are rather uniformly distributed in chromatin (4-6). Prominent examples are pyrimidine dimers induced by ultraviolet (UV) light and DNA adducts generated by chemical carcinogens. In particular, UV radiation is the most common environmental genotoxic agent and the major etiological factor for the development of skin cancer (7). Depending on the locality, season, time of day, weather conditions and the period of exposure, an assault by the shortwave sunlight spectrum generates in each skin cell hundreds of thousands of covalent crosslinks between neighboring pyrimidines, predominantly cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PPs) in a stoichiometry of ~4:1 (7-9). The multipronged cellular responses to this genotoxic insult can only be understood when analyzed in the physiologic context of the tightly packed chromatin substrate.