PNAS: There is a new understanding of the nucleotide excision repair process

Nucleotide cut repair (NER) is a major DNA-conserved repair pathway that repairs various types of damage in the genome, such as damage
caused by ultraviolet light and environmental factors.
Dysfunction of this route can be harmful
to human health.
For example, people with NER defects have pigmented dry dermatosis, a disease characterized by an extreme predisposition to sunlight-induced skin cancer due to the inability to repair UV-damaged DNA
.

Therefore, while NER can fight cancer formation, it is also important
to treat tumors.
Many antineoplastic drugs, such as cisplatin, induce DNA damage that can be repaired by NER
.
In this case, NER is a drug target to improve the effectiveness of cancer treatment
.
At the molecular level, NER is a highly complex and dynamic molecular machine involving more than 30 proteins that aggregate at the site of DNA damage to remove damage and replace it
with intact DNA.
This process is guided by protein-protein-DNA interactions
.

By Deputy Director Orlando D.
Sch? A research team led by RER and KIM Mihyun, a graduate student at the Center for Genomic Integrity at the Korea Institute of Basic Science, explored these interactions
.
The team found that two key proteins in NER, the colored dry dermatitis protein A (XPA) and the replication protein A (RPA), are necessary for the incision precomplex in the tissue NER
.

After the damage in DNA was discovered, two proteins, XPA and RPA, were responsible for organizing the NER complex
.
This study compares mutant variants of these two proteins to investigate how these two proteins are involved in key interactions of
the NER pathway.
Specifically, we found that the two interfaces between XPA and RPA are critical to NER and have different roles
in the pathway.
The interaction of XPA with RPA32 is critical for the initial association of XPA with DNA damage, while the interaction of XPA with RPA70 is critical for the completion of NER
.

Comprehensive structural studies of the XA-RPA-DNA Complex reveal how the interaction of these two proteins forms the NER complex and triggers the excision
of injury.
The interaction of XPA and RPA32 occurs on the periphery of the complex, where it promotes the initial assembly
of the protein at the site of injury.
The interaction between XPA and RPA70 is located in the center of the NER complex, forcing the DNA to take a U-shape
.
This makes the two ss/dsDNA connections very close together, allowing the NER complex to cut DNA to remove damage
.

Deputy Director Orlando D.
SCH? RER said: "Our study reveals a surprising new model of the NER complex and how the interaction between XPA and RPA shapes its structure
.
Disrupting the interaction between XPA and RPA can inhibit NER, and our study provides a blueprint
for how small molecules can target this interaction to improve cancer treatment.
" We will continue our follow-up research
with our long-term partner, Professor Walter Chazin of Vanderbilt University.
”

essay

Two interaction surfaces between XPA and RPA organize the preincision complex in nucleotide excision repair