Ubiquitin at work: the ubiquitous regulation of the damage recognition step of NER.

Nucleotide excision repair (NER) removes a wide variety of helix distorting DNA lesions. NER comprises two damage recognition sub-pathways: GG-NER operates genome wide, whereas TC-NER specifically removes transcription-blocking lesions from the transcribed strand of actively transcribed genes. NER is a multistep process, which requires the concerted action of 30 proteins that need to be tightly controlled at the right time and place for efficient repair. Post-translational protein modifications (PTMs) are common regulators of complex protein networks. Several NER factors were shown to be modified by ubiquitin, whereas others are actively involved in the ubiquitin-proteasome system itself. PTMs by ubiquitylation can be swiftly induced in a reversible manner and have the ability to regulate protein function, localization or stability. This makes the regulation by ubiquitin highly suitable for the coordination of the complex NER reaction. Accumulating evidence, including proteome wide quantitative proteomics approaches, showed that especially NER factors involved in the damage recognition are regulated by ubiquitin, emphasizing the high level of regulation during the initiation of the NER reaction. In this review we will therefore focus on the different functions of ubiquitylation during the DNA damage recognition steps of NER.