Terminally differentiated cells need never replicate their genomes and may therefore dispense with the daunting task of maintaining several repair systems to constantly scan their entire complement of DNA. Obviously, transcribed genes need to be repaired, so that cells can carry out their specialized functions, but dedicated mechanisms such as transcription-coupled repair and differentiation-associated repair can ensure the maintenance of those transcriptionally active domains. Many groups have studied DNA repair in differentiated cells, often with divergent results, possibly because there are distinct classes of differentiated cells, with unique properties. Thus neurons ought to last for a lifetime, whereas myocytes are backed by precursor cells, while white blood cells like macrophages are constantly being replaced. More importantly, different DNA repair systems can vary in their response to cellular differentiation, possibly depending on whether they can be coupled to transcription. Nucleotide excision repair (NER) is probably the most versatile DNA repair system and is coupled to transcription. NER was shown to be attenuated by differentiation in several cell types, including neurons. The attenuation occurs only at the global genome level, with transcribed genes still being efficiently repaired. We have determined that this attenuation results from the lack of ubiquitination of a NER factor, most likely owing to differences in phosphorylation of the ubiquitin-activating enzyme E1. Because there is only one E1 in human cells, it is likely that other metabolic pathways are similarly affected, depending on whether they rely on an E2 enzyme which is sensitive to the state of E1 phosphorylation.