XPC-RAD23B enhances UV-DDB binding to DNA to facilitate lesion search in nucleotide excision repair

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Abstract
Ultraviolet-induced DNA lesions are removed by the nucleotide excision repair (NER) pathway. In global-genome NER (GG-NER), XPC-RAD23B recognizes the lesions and initiates NER. However, cyclobutane pyrimidine dimers (CPDs), which do not significantly destabilize the DNA duplex, are not bound by XPC-RAD23B with high selectivity. Instead, CPD is preferentially sensed by UV-DDB, which is believed to hand over the lesion to XPC-RAD23B via ubiquitination of both proteins. Here, by combining biochemical and single-molecule DNA curtain assays, we investigate the interactions between UV-DDB and XPC-RAD23B on DNA. Surprisingly, we discover that XPC-RAD23B enhances the binding of UV-DDB to DNA. We demonstrate that this enhancement can be attributed to the complex formation of UV-DDB and XPC-RAD23B (UX-complex), which increases the binding affinity of UV-DDB to undamaged DNA. We further show that UV-DDB finds CPDs through one-dimensional (1D) diffusion along DNA. Collectively, the UX-complex enhances UV-DDB loading to DNA to accelerate the search for CPD via 1D diffusion. Moreover, we find that UV-DDB and XPC-RAD23B can bind CPDs as a complex, which facilitates the transfer of CPD. Altogether, our results show that UV-DDB and XPC-RAD23B cooperatively interact for rapid CPD search, providing a new mechanism for lesion search in GG-NER.
Funding Information
  • National Research Foundation of Korea (RS-2024-00449988, RS-2024-00509412)
  • Korea Basic Science Institute
  • Ministry of Science and ICT (RS-2024-00401816)
  • Ministry of Education (2021R1A6C101A442)
  • Korean Institute for Basic Science (IBS-R022-A1)
  • National Cancer Institute (P01-CA092584)
  • KAKENHI (JP21H03598, JP21K17889)
  • Cosmetology Research Foundation (837)
  • JST (JPMJSP2148)

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