Scientists achieve a new understanding of the nucleotide excision repair process
Distinct role of the interactions of RPA32 and RPA70 with XPA in NER. Cells were irradiated with UV and the colocalization of XPA with UV damage sites was visualized by fluorescence microscopy. DNA damage is highlighted by red arrows and co-localization of XPA with UV DNA is indicated by yellow arrows. In XPA-RPA32 mutant cells (M32-4), reduced XPA recruitment to DNA damage was observed. In XPA-RPA70 mutant cells (M70-6), XPA remained bound at damaged sites for an extended time. This indicates that RPA32 interaction with XPA is required for recruitment of XPA to UV-induced damage, while RPA70 interaction with XPA is important for positioning of XPA for completion of NER. Credit: Institute for Basic Science

The ner is a major conserved pathway that repairs various types of damage in the genome. Human health can be adversely affected by this pathway being disrupted. xeroderma pigmentosum is a disease characterized by an extreme disposition to sunlight and is caused by an inability to repair UV- damaged DNA.

It's important that NER counteracts cancer formation. cisplatin can cause damage to DNA that can be repaired by ner. Drug targets of interest to improve cancer therapy outcomes are ner. NER is a highly complex and dynamic machine that involves over 30 proteins that assemble at DNA lesions to excise the damage and replace it with intact DNA The process is guided by the interaction of two genes.

The Institute for Basic Science, South Korea has a team of researchers led by the Associate Director. The team found that the pre-incision complex in NER requires two key proteins.

The organization of the NER complex can be traced back to the discovery of damage in DNA. The study looked at how the two proteins interact with each other. It was found that there are distinct roles in the pathway for the two interaction interface between the two. The initial association of XPA with DNA damage is dependent on the interaction between the two.

Scientists achieve a new understanding of the nucleotide excision repair process
Structure of the NER pre-incision complex. The interaction of XPA and RPA70 is localized in the center of the NER complex, while the interaction site of XPA and RPA32 is at the periphery. The interactions between XPA and RPA70 stabilize the pre-incision complex and constricts the DNA to assume a U-shape, which appears to be the active form of the complex, allowing it to remove the DNA damage. Credit: Institute for Basic Science

Structural studies of an XPA-RPA-DNA complex showed how the interaction of the two proteins shapes the NER complex. The initial assembly of the proteins at the site of damage is aided by the interaction of the two genes. The DNA is forced into a U-shape by the interaction between the two genes. The NER complex can incise the DNA to remove the damage if the two ss/dsDNA junctions become local.

According to Schrer, their study revealed a new model of the NER complex and how it is shaped by the interaction between XPA and RPA. Our study shows how disrupting the interaction between the two drugs can be used to improve cancer therapy. We are working on follow-up research with our long-term partner Prof. Walter Chazin.

The research was published in the national academy of sciences

More information: Mihyun Kim et al, Two interaction surfaces between XPA and RPA organize the preincision complex in nucleotide excision repair, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2207408119 Journal information: Proceedings of the National Academy of Sciences
XPANERNER complexDNA
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