How cells select DNA damage repair pathways

Newswise — DNA is widely recognized as the life's plan, vital for an entity to enable vital activities. DNA can suffer harm from diverse elements like radical metabolites, radiation, and certain noxious substances. Being a molecule composed of two strands, either single or both strands can undergo harm.

Single-strand break (SSB) arises when one DNA strand undergoes harm or fracture. These damages are relatively moderate and can be promptly repaired by specific enzymes that can mend the break and reinstate the wholeness of the DNA structure. Conversely, a double-strand break (DSB) denotes the impairment of both DNA strands. Such instances are deemed the utmost critical form of DNA damage, with the potential to induce genetic mutations or cellular demise.

Cells uphold genome integrity through the presence of diverse pathways for mending DSBs. Amidst the numerous mechanisms for DSB repair, homologous recombination repair (HR) stands out as a remarkably accurate and faultless process, utilizing the intact sister chromatid as a template for DSB mending. Conversely, DNA mended via polymerase theta-mediated end-joining (TMEJ) may lead to the loss of genetic information and give rise to mutations. Thus, selecting the suitable DSB repair process is pivotal for preserving genome integrity.

But How do cells select the right repair process? And what kinds of proteins are involved in the selection process?

Under the guidance of Professor MYUNG Kyungjae, who serves as the Director of the Center of Genomic Integrity (CGI) in the Institute for Basic Science (IBS), the research groups led by Professor LEE Ja Yil at Ulsan National Institute of Science and Technology, and Professor OH Jung-Min at Pusan National University, have unveiled a significant finding. They have uncovered a close relationship and interaction among repair proteins engaged in DSB repair, mismatch repair, and TMEJ during the process of repairing DSBs.

Within our cells, a multitude of repair mechanisms exist, each customized to address specific types of DNA damage. For example, DSBs are rectified by DSB repair proteins, whereas inaccurately paired DNA bases are mended by mismatch repair proteins. Until recently, the prevailing belief among researchers was that each form of DNA damage is exclusively repaired by its corresponding DNA repair mechanism.

Nonetheless, this study has uncovered a groundbreaking revelation, indicating that repair proteins, previously believed to be exclusively responsible for distinct repair mechanisms, are capable of interacting with one another. These interactions enable them to identify damaged sites and collectively determine the most suitable repair mechanism for the given situation. Consequently, the traditional notion of repair proteins being confined to specific repair pathways has been challenged by these findings.

The study specifically shed light on the significant involvement of MSH2-MSH3, a DNA mismatch repair protein, in the DSB repair process. Remarkably, the researchers observed that fluorescent protein-labeled MSH2-MSH3 protein is recruited to the precise location of DSBs. This recruitment was found to occur through its interaction with a chromatin remodeling protein known as SMARCAD1. The binding between MSH2-MSH3 and DSBs facilitates the subsequent recruitment of EXO1 (exonuclease 1), which is crucial for carrying out long-range resection of the damaged DNA. These findings unveil the previously unrecognized role of MSH2-MSH3 in facilitating DSB repair.

Following the long-range resection process, the damaged DNA undergoes error-free HR for repair. Notably, the study also revealed that the binding of MSH2-MSH3 has an additional crucial role. It inhibits the access of POLθ, which is responsible for mediating a more error-prone TMEJ pathway. By doing so, the binding of MSH2-MSH3 effectively prevents the occurrence of mutations that may arise during the DSB repair process. This finding highlights the important regulatory function of MSH2-MSH3 in safeguarding the fidelity of DSB repair and minimizing the risk of detrimental genetic alterations.

Director Myung expressed, "This research has unveiled a novel role of the mismatch repair protein MSH2-MSH3 in the regulation of DSB repair." He further emphasized, "The repair proteins, which were previously thought to operate independently in the mismatch repair, double-stranded break repair, and TMEJ repair pathways, are now demonstrated to closely interact with each other to ensure the appropriate maintenance of genomic integrity." This statement underscores the significance of the study's findings in reshaping our understanding of the collaborative nature of repair proteins and their essential role in preserving the integrity of the genome.

This work was published in Nucleic Acids Research on May 4th, 2023.