Study reveals key mechanism behind DNA repair processes

According to a study recently published in the eLife journal, researchers have demonstrated a crucial mechanism involved in the repair processes of DNA double-strand breaks.

This latest finding will help one’s interpretation of why the repair processes of DNA do not work correctly in a specific section of people, leading to cancer and inherited diseases.

DNA Repair

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Homologous recombination (HR) is one of the most important DNA repair processes. It has the ability to repair a severe form of DNA damage in which both DNA strands are damaged. HR is regulated by a protein called Rad51, which, in turn, is supported by many “helper” proteins.

We already know that a group of helper proteins can be sub-grouped into two modules, and that each module has a different role. In this study, we aimed to understand exactly how Module 1 interacts with Rad51 and how the two modules cooperate to switch on Rad51.”

Bilge Argunhan, Study Lead Author and Researcher, Tokyo Institute of Technology

Argunhan is working in senior author Hiroshi Iwasaki’s laboratory at Japan-based Tokyo Institute of Technology.

The scientists initially used yeast cells to examine the Rad51 protein as well as its helper proteins, known as Swi5-Sfr1. Then, they genetically modified the yeast cells and made sure that these cells do not contain either Module 1 or Module 2 of Swi5-Sfr1. The team eventually observed that this technique inhibited HR from repairing the DNA, demonstrating that both modules are required for the Rad51 protein to activate HR repair.

The scientists next purified the Swi5-Sfr1 helper proteins from yeast cells to detect the exact regions within Module 1 that bind to the Rad51 protein. Then, by mutating the sequence of proteins, the team successfully altered these regions, which prevented the Swi5-Sfr1 from binding to the Rad51 protein.

To their surprise, the researchers discovered that, while the mutated helper proteins were not able to switch on the Rad51 protein in a test tube, yet the mutated yeast cells were able to fix their DNA without any issue. This discovery made the researchers speculate that another set of helper proteins, which are absent in the test tube but present in the cell, was involved in the DNA repair process.

Prior genetic researches had demonstrated that yeast contains two HR sub-pathways—one pathway that relies on Swi5-Sfr1, and another that depends on molecules known as Rad51 paralogs. To find out whether the HR pathway is responsible for rescuing the DNA repair mechanism, the researchers studied yeast in which the Rad51 paralogs were absent.

The outcomes were remarkable: the DNA damage was relatively more severe in yeast that lacked Rad51 paralogs but contained the mutant Swi5-Sfr1. This indicates that thesecond group of helper proteins suppresses the damaging impacts of mutations on the Swi5-Sfr1 helper complex.

Although these two groups of helper proteins were previously thought to function independently, our study shows that they actually work together to activate Rad51 in DNA repair. The fundamental mechanisms of DNA repair are highly conserved from yeast to humans. Our new insight into DNA repair in yeast may serve as a template for understanding why DNA repair processes do not function properly in human disease.”

Hiroshi Iwasaki, Study Senior Author and Professor, Tokyo Institute of Technology

Source:
Journal reference:

Argunhan, B., et al. (2020) Cooperative interactions facilitate stimulation of Rad51 by the Swi5-Sfr1 auxiliary factor complex. eLife. doi.org/10.7554/eLife.52566.

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