Higher understanding of the mechanisms involved in DNA repair may pave the way in which for developing inhibitors to enhance the effectiveness of radiation therapy.

Nucleotide excision repair (NER) is a critical DNA repair pathway that plays a key role in maintaining transcription and genome integrity by removing bulky DNA lesions.

The important thing steps within the NER response include damage recognition, strand separation by the molecular motor TFIIH and excision of about 30 nucleotides by the nucleases XPG and XPF, which removes the damage and allows transcription to proceed without DNA damage signaling occurring. But how these steps are coordinated and controlled shouldn’t be well understood.

Now, a big advance in showing how the NER mechanism is controlled on the molecular level has been identified in a study by a world team led by researchers at KAUST and the University of Texas MD Anderson Cancer Center.

The work is potentially significant for cancer treatment, Ph.D. student and the study’s lead creator Amer Bralić explains.

“During radiation therapy, cancer cells are blasted with radiation to shrink tumors. In this case, nevertheless, NER works against the treatment, attempting to repair the damage and stopping cell death, which significantly reduces the effectiveness of the treatment.”

For a few years, researchers have sought a biologically protected NER inhibitor that might be given to cancer patients to extend the effectiveness of radiation treatment. Nevertheless, a big obstacle in designing inhibitors is the dearth of basic knowledge in regards to the NER mechanism. Samir Hamdan’s group at KAUST are experts in single-molecule evaluation of human DNA replication and repair and have used this system to disclose how 30 proteins mediate NER.

They’ve uncovered how TFIIH uses XPG to stimulate its motor activity to locate damaged DNA. In turn, once TFIIH locates the damage, it licenses the XPG nuclease activity to excise it. This significant discovery was chosen as a “breakthrough article” by the journal Nucleic Acids Research. “The finding unravels a fundamental control mechanism in NER and argues for tackling the interaction between TFIIH and XPG as an efficient drug goal,” says Hamdan.

A posh mutation landscape in NER proteins mediates greater than 10 clinical diseases, where mutations in a single protein may cause different diseases and different mixtures of proteins may cause one disease.

Our mechanistic findings provide latest perspectives on linking molecular level information to disease states.”

Amer Bralić, Study’s Lead Writer

“Through the KAUST Smart Health Initiative, we are going to work with clinicians within the Kingdom to review the clinical mutational landscape of NER proteins in patients,” concludes Hamdan.

Source:

KAUST – King Abdullah University of Science and Technology

Journal reference:

Bralić, A., et al. (2022) A scanning-to-incision switch in TFIIH-XPG induced by DNA damage licenses nucleotide excision repair. Nucleic Acids Research. doi.org/10.1093/nar/gkac1095.