DNA is usually regarded as the blueprint for life and is essential for an organism to perform biological tasks. A range of factors, including radical metabolites, radiation, and other hazardous substances, can cause DNA damage. Because DNA is a two-stranded molecule, it can be damaged on either one or both strands.
A single-strand break (SSB) happens when one of the two strands of DNA is damaged or broken. These are tiny defects that can be promptly repaired by specialised enzymes that seal the break and restore the integrity of the DNA molecule. In contrast, a double-strand break (DSB) occurs when both strands of DNA are broken. These are the most severe types of DNA damage, capable of causing genetic changes or cell death.
Cells preserve genomic integrity by having many repair mechanisms for DSBs. Among the several DSB repair processes, homologous recombination repair (HR) is a highly accurate and error-free technique that employs the undamaged sister chromatid as a template to repair DSBs. However, DNA repair through polymerase theta-mediated end-joining (TMEJ) might result in the loss of some genetic material and the development of mutations. To maintain genomic integrity, selecting the optimal DSB repair method is critical.
But How do cells select the right repair process? And what kinds of proteins are involved in the selection process?
Led by Professor MYUNG Kyungjae, Director of the Center of Genomic Integrity (CGI) within the Institute for Basic Science (IBS), the research teams of Professor LEE Ja Yil at Ulsan National Institute of Science and Technology, and Professor OH Jung-Min at Pusan National University have discovered that repair proteins involved in DSB repair, mismatch repair, and TMEJ are closely related and interact with each other during DSB repair process.
There are various repair mechanisms in our cells, each tailored to the type of DNA damage. For instance, DSBs are repaired by DSB repair proteins, while improperly paired DNA bases are repaired by mismatch repair proteins. Until now, most researchers thought that a specific type of DNA damage is only repaired by its corresponding DNA repair mechanism.
However, this study revealed that repair proteins previously thought to be responsible for different repair mechanisms can interact with each other to recognize damaged sites and select an appropriate repair mechanism.
Specifically, it was revealed that MSH2-MSH3, a DNA mismatch repair protein, plays a crucial role in the DSB repair process. The researchers observed the recruitment of fluorescent protein-labelled MSH2-MSH3 protein to the site of DSBs and revealed that this movement occurs through binding with the chromatin remodelling protein called SMARCAD1. The binding of MSH2-MSH3 to DSBs facilitates the recruitment of EXO1 (exonuclease 1) for long-range resection of damaged DNA.
After the long-range resection, the damaged DNA is repaired through error-free HR. Furthermore, it was discovered that the binding of MSH2-MSH3 inhibits the access of POLth, which mediates a more error-prone TMEJ pathway, thereby preventing mutations that may occur during DSB repair.
Director Myung said, "This research has revealed a new function of the mismatch repair protein MSH2-MSH3 in regulating DSB repair," adding, "The repair proteins that have been believed so far to act independently in the mismatch repair, double-stranded break repair, and TMEJ repair pathways are now shown to interact each other for proper maintenance of genomic integrity closely." (ANI)