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

Nucleotide excision repair (NER) is a major conserved DNA repair pathway, which repairs various types of damage in the genome, such as those induced by ultraviolet light and environmental agents. Dysfunction in this pathway can be detrimental to human health. For example, individuals with defects in NER suffer from xeroderma pigmentosum, a disease characterized by an extreme disposition to sunlight-induced skin cancer due to an inability to repair UV-damaged DNA.

While NER thus counteracts cancer formation, it is also important for antitumor therapy. Many antitumor agents, such as cisplatin, induce damage to DNA that can be repaired by NER. In this context, NER is a drug target of interest to improve cancer therapy outcomes. At the molecular level, NER is a highly complex and dynamic molecular machine, involving over 30 proteins that assemble at DNA lesions to excise the damage and replace it with intact DNA. This process is guided by protein-protein and protein-DNA interactions.

A team of researchers led by the Associate Director Orlando D. Schärer and graduate student Kim Mihyun of the Center for Genomic Integrity within the Institute for Basic Science, South Korea explored these interactions. The team found that two key proteins in NER, namely xeroderma pigmentosum protein A (XPA) and replication protein A (RPA) proteins, are required for organizing the pre-incision complex in NER.

The two proteins XPA and RPA are responsible for the organization of the NER complex after it has found the damage in DNA. The present study compared mutant variants of these two proteins to investigate how the two proteins engage in a pivotal interaction for the NER pathway. Specifically, it was discovered that two interaction interfaces between XPA and RPA are critical for NER and have distinct roles in the pathway. The interaction of XPA with RPA32 is crucial for the initial association of XPA with DNA damage, whereas the interaction between XPA and RPA70 is important for the completion of NER.

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

Integrative structural studies of an XPA-RPA-DNA complex revealed how the interactions of the two proteins shape the NER complex and trigger excision of the damage. The interaction of XPA and RPA32 occurs at the periphery of the complex, where it facilitates the initial assembly of the proteins at the site of damage. The interaction between XPA and RPA70 is located at the heart of the NER complex and forces the DNA into a U-shape. This allows the two ss/dsDNA junctions to become localized in close proximity, allowing for the NER complex to incise the DNA to remove the damage.

Schärer stated that their “study revealed a surprising new model of the NER complex and how the interaction between XPA and RPA shapes its architecture. 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.”

This research was published in Proceedings of 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

Provided by Institute for Basic Science Citation: Scientists achieve a new understanding of the nucleotide excision repair process (2022, September 27) retrieved 27 September 2022 from https://phys.org/news/2022-09-scientists-nucleotide-excision.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

TECH NEWS RELATED

Black Friday Is Over, but These 9 Record-Low Deals Are Still Here Ahead of Cyber Monday

You just won't find better deals this Black Friday weekend.

View more: Black Friday Is Over, but These 9 Record-Low Deals Are Still Here Ahead of Cyber Monday

Cyber Monday Sale Drops the Backbone Mobile Game Controllers to $65. That's a Steal

The Backbone One game controllers, which snap on to your phone, are among the best I've ever used, and certainly in the top two for iPhones.

View more: Cyber Monday Sale Drops the Backbone Mobile Game Controllers to $65. That's a Steal

Cyber Monday Deals Ahead: Black Friday Sales on Google Gadgets Are Still Going Strong

Take advantage of these Cyber Monday discounts on Google Store gadgets like Pixel phones and Nest products.

View more: Cyber Monday Deals Ahead: Black Friday Sales on Google Gadgets Are Still Going Strong

100-Plus Deals to Keep an Eye on Ahead of Cyber Monday

Amazon has switched focus to Cyber Monday, but most of its Black Friday deals are still up for grabs.

View more: 100-Plus Deals to Keep an Eye on Ahead of Cyber Monday

Scientists Reveal That This Type of Dating Profile Sparks More Attraction

The study found that originality in an online dating profile text improves evaluations of personality and attractiveness. Additionally, owners of “original” profiles are rated as being smarter, funnier, and more likable. A new study of online dating site users found a correlation between the perceived originality of text in dating ...

View more: Scientists Reveal That This Type of Dating Profile Sparks More Attraction

Orion captures haunting pictures of the Lunar surface

NASA’s Artemis I mission lifted off from Earth just a few short weeks ago, and since then, the Orion capsule has captured a breathtaking view of Earth and even completed its lunar flyby. While preparing to enter what NASA calls a distant retrograde orbit, the Orion capsule also managed ...

View more: Orion captures haunting pictures of the Lunar surface

These Super Secret Cyber Monday Deals Require Your Voice to Access Them

Want some secret deals? Ask Alexa and order with your voice.

View more: These Super Secret Cyber Monday Deals Require Your Voice to Access Them

Take Advantage of This Disney Plus Deal for Black Friday and Cyber Monday

Ford’s New Electric Van Tows Your Family Into the Future

How to Use Google Drive Files Offline on Mac

The links between viruses and Alzheimer’s were dismissed for years – but evidence is building

Chinese Vessel With Largest-ever Cannon Entered Japan Territory Near Disputed Senkakus

Astronomers Discover Important New Information Regarding Star Formation

Mind the gaps: The world needs to radically transform its educational systems, not just upgrade them

Black Friday Target Deals Still Live: Price Drops Ahead of Cyber Monday

Why Amazon's Alexa and Echo Devices Might Not Be Profitable? Here are Some Reasons

The 7 Best Roblox Gifts for Holiday 2022

5 new Netflix releases you better not miss next week

10 Best Ways to Fix Spatial Audio Not Working on AirPods 3 or AirPods Pro

How satellites, radar and drones are tracking meteorites and aiding Earth's asteroid defense

OTHER TECH NEWS

Top Car News Car News