Scrima, A. et al. Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex. Cell 135, 1213-1223

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH 4058 Basel, Switzerland.
Cell (Impact Factor: 32.24). 01/2009; 135(7):1213-23. DOI: 10.1016/j.cell.2008.10.045
Source: PubMed


Ultraviolet (UV) light-induced pyrimidine photodimers are repaired by the nucleotide excision repair pathway. Photolesions have biophysical parameters closely resembling undamaged DNA, impeding discovery through damage surveillance proteins. The DDB1-DDB2 complex serves in the initial detection of UV lesions in vivo. Here we present the structures of the DDB1-DDB2 complex alone and bound to DNA containing either a 6-4 pyrimidine-pyrimidone photodimer (6-4PP) lesion or an abasic site. The structure shows that the lesion is held exclusively by the WD40 domain of DDB2. A DDB2 hairpin inserts into the minor groove, extrudes the photodimer into a binding pocket, and kinks the duplex by approximately 40 degrees. The tightly localized probing of the photolesions, combined with proofreading in the photodimer pocket, enables DDB2 to detect lesions refractory to detection by other damage surveillance proteins. The structure provides insights into damage recognition in chromatin and suggests a mechanism by which the DDB1-associated CUL4 ubiquitin ligase targets proteins surrounding the site of damage.

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    • "Consistently, our previous transgenic study demonstrated that, like tomato DDB1, the down-regulation of tomato CUL4 results in an elevated plastid level and overproduction of pigments (Wang et al., 2008). In theory , DDB1 could either directly dock a substrate protein and regulate its ubiquitination or recruit a substrate target via an additional adaptor (Li et al., 2006; Scrima et al., 2008). In the case of ubiquitination/degradation of GLK2, the former seems likely to be due to the positive result of BiFC analyses that are known to work for direct interactions mediating a re-construction of the YFP fluorescence activity (Fig. 4c). "
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    • "There are two subpathways in eukaryotic NER: global genome NER (GG-NER) and transcription-coupled NER (TC-NER)2. In GG-NER, the XPE protein, which consists of the DDB1 and DDB2 subunits, recognizes the lesion by forming a specific complex with damaged DNA5, and then the DNA is transferred to the XPC protein, through the ubiquitylation of both proteins by the ubiquitin ligase bound to DDB16. After this damage recognition step, TFIIH, a general transcription factor, and the XPA protein are recruited. "
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