Researchers at Georgia State University have been utilizing the Summit supercomputer to simulate the intricate process of DNA repair, specifically focusing on nucleotide excision repair (NER).

NER operates through three critical stages: damage recognition by the XPC protein, verification by TFIIH, and repair facilitated by the pre-incision complex (PInC), each requiring specific proteins to function effectively.

In this process, XPC identifies DNA damage and prepares it for repair, while TFIIH unwinds the DNA and scans for lesions, enabling PInC to remove the damaged sections.

The study highlights the significance of PInC within NER, which is essential for regulating DNA repair processes.

To construct the PInC model, researchers employed cryo-electron microscopy data alongside the neural network model AlphaFold2 to predict unknown protein structures.

Molecular dynamics simulations conducted using NAMD on the Summit supercomputer provided valuable insights into the functional dynamics of PInC and its components.

The findings from this research offer a deeper understanding of the mutations affecting NER, particularly in the dynamic regions of the protein complexes involved.

Lead investigator Ivaylo Ivanov emphasized the complexity of NER, noting that mutations in repair proteins can lead to a range of human diseases, including UV sensitivity and premature aging.

Mutations in the enzymes XPF and XPG, which play a role in the NER process, can result in serious genetic disorders such as xeroderma pigmentosum and Cockayne syndrome.

Given that DNA can be damaged by UV radiation and carcinogens, understanding the mechanisms of DNA repair is vital for advancing treatment options for severe health issues, including cancer.

Published in Nature Communications, this research aims to identify new therapeutic targets for diseases associated with DNA damage and aging.

Following the retirement of the Summit supercomputer at the end of 2024, the research team plans to continue their work using its successor, Frontier, with a focus on transcription-coupled NER.