Genome-wide impact of DDB2 on the repair of UV-induced DNA lesions

Although damage-specific DNA binding protein 2 (DDB2) facilitates damage recognition and chromatin remodeling during global genome nucleotide excision repair (GGR) in vivo, it is dispensable for the GGR reaction in vitro. Nonetheless, mutations in DDB2 cause xeroderma pigmentosum (XP), an inherited disorder resulting from defective GGR. Proposed mechanisms by which DDB2 facilitates GGR in vivo include bending the DNA helix to promote xeroderma pigmentosum complementation group C (XPC) recruitment at mildly distorted lesions, remodeling chromatin structures to allow XPC binding, and ubiquitinating itself and XPC to enhance damage recognition and handover. However, how DDB2 coordinates with distinct chromatin environments to repair different lesions remains unclear. Here, we generated genome-wide repair maps of UV-induced cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PPs) in human cells with and without DDB2, and assessed the impact of DDB2 across multiple chromatin scales. Our results indicate that DDB2 reduces the genomic heterogeneity of CPD repair by preferentially promoting repair in compact chromatin regions at different levels. In contrast, DDB2 exerts only a subtle influence on 6-4PP repair, primarily affecting repressed regions at small scales, such as nucleosome core particles and regions marked by inactive histone modifications. In summary, this study provides new insights into the genomic functions of DDB2 and illuminates future investigations into the coordination between GGR and chromatin context.