Study Reveals Mechanisms Behind Nucleotide Excision Repair

Nucleotide excision repair, or NER, clears genomes of damage occurring via UV light, environmental agents, and antitumor drugs. Dysfunction within this pathway has been observed to be detrimental to human health while simultaneously counteracting the efficacy of antitumor agents. For a more detailed understanding of NER’s cellular mechanisms, researchers from the Center for Genomic Integrity within the Institute for Basic Science in South Korea investigated which proteins play a significant role in these interactions.

Many antitumor agents induce DNA damage that NER can later repair. As such, NER is a drug target of interest for researchers aiming to improve cancer therapy outcomes. At the molecular level, NER is a dynamic and highly complex molecular machine that involves over 30 different proteins that assemble at sites of DNA damage. The damaged segments can then be removed before replacing them with intact DNA. This complex process is carefully controlled with protein-protein and protein-DNA interactions. 

While there has been a lot of work trying to uncover more about this process, many of the molecular mechanisms remained unclear. However, a research team led by Associate Director Orlando D. Schärer and graduate student Kim Mihyun found two key proteins involved in NER – xeroderma pigmentosum protein A (XPA) and replication protein A (RPA.)

Both proteins were found to be responsible for organizing the NER complex after damage occurs in DNA. The study, which was published in the journal Proceedings of the National Academy of Sciences, compared mutant variants of these two proteins to see how they engage in a pivotal interaction for the NER pathway.

The researchers discovered that two interaction interfaces between RPA and XPA are crucial for NER, each with its own distinctive role in the pathway. Additionally, the interaction of XPA and RPA C-terminal domain (RPA32C) is essential for the initial association of XPA with DNA damage. In contrast, the interaction between XPA and RPA70 is vital for the completion of NER.

“Our study revealed a surprising new model of the NER complex and how the interaction between XPA and RPA shapes its architecture,” says Schärer. “Disruption of the interaction between XPA and RPA inhibits NER, and our study provides a blueprint for how this interaction may be targeted by small molecules to improve cancer therapy. We are continuing to pursue follow-up research together with our long-term collaborator on this project, Prof. Walter Chazin at Vanderbilt University.”