Xeroderma pigmentosum (XP) is a heritable human disorder characterized by 
defects in nucleotide excision repair (NER) and the development of skin cancer. 
Cells from XP group E (XP-E) patients have a defect in the UV-damaged 
DNA-binding protein complex (UV-DDB), involved in the damage recognition step of 
NER. UV-DDB comprises two subunits, products of the DDB1 and DDB2 genes, 
respectively. Mutations in the DDB2 gene account for the underlying defect in 
XP-E. The UV-DDB complex is a component of the newly identified cullin 4A-based 
ubiquitin E3 ligase, DDB1-CUL4A(DDB2). The E3 ubiquitin ligases recognize 
specific substrates and mediate their ubiquitination to regulate protein 
activity or target proteins for degradation by the proteasomal pathway. In this 
study, we have addressed the role of the UV-DDB-based E3 in NER and sought a 
physiological substrate. We demonstrate that monoubiquitinated histone H2A in 
native chromatin coimmunoprecipitates with the endogenous DDB1-CUL4A(DDB2) 
complex in response to UV irradiation. Further, mutations in DDB2 alter the 
formation and binding activity of the DDB1-CUL4A(DDB2) ligase, accompanied by 
impaired monoubiquitination of H2A after UV treatment of XP-E cells, compared 
with repair-proficient cells. This finding indicates that DDB2, as the substrate 
receptor of the DDB1-CUL4A-based ligase, specifically targets histone H2A for 
monoubiquitination in a photolesion-binding-dependent manner. Given that the 
loss of monoubiquitinated histone H2A at the sites of UV-damaged DNA is 
associated with decreased global genome repair in XP-E cells, this study 
suggests that histone modification, mediated by the XPE factor, facilitates the 
initiation of NER.