Biotechnology

How cells choose pathways to repair DNA damage


DNA is known as the blueprint of life, which is necessary for an organism to facilitate life processes. DNA can be damaged by various factors such as radical metabolites, radiation, and some toxic chemicals. Since DNA is a molecule consisting of two strands, one or both strands can be damaged.

DNA is known as the blueprint of life, which is necessary for an organism to facilitate life processes. DNA can be damaged by various factors such as radical metabolites, radiation, and some toxic chemicals. Since DNA is a molecule consisting of two strands, one or both strands can be damaged.

Single-strand break (SSB), occurs when one of the two strands of DNA is damaged or breaks. This is relatively minor damage that can be easily repaired by special enzymes that can seal the damage and restore the integrity of the DNA molecule. On the other hand, double-strand break (DSB) refers to when both DNA strands are broken. It is considered the most severe type of DNA damage, capable of causing genetic mutations or cell death.

Cells maintain genome integrity by having multiple pathways for repairing DSBs. Among several mechanisms to repair DSB, homologous recombination (HR) repair is one of the most precise and error-free mechanisms, since it uses undamaged sister chromatids as a template for DSB repair. On the other hand, DNA repair by polymerase theta-mediated end-joining (TMEJ) can result in the loss of some genetic information and cause mutations. Therefore, it is very important to choose the right DSB repair process to maintain genome integrity.

But How does the cell choose 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 team Professor LEE Ja Yil at Ulsan National Institute of Science and Technology, and Professor OH Jung-Min at Pusan ​​National University​ have found that the repair proteins involved in DSB repair, mismatch repair, and TMEJ are closely related and interact with each other during the DSB repair process.

There are various repair mechanisms in our cells, each adapted to the type of DNA damage. For example, DSBs are repaired by DSB repair proteins, while mismatched DNA bases are repaired by mismatch repair proteins. Until recently, most researchers thought that certain types of DNA damage could only be repaired by suitable DNA repair mechanisms.

However, this study reveals that repair proteins previously thought to be responsible for different repair mechanisms can interact with each other to recognize damaged sites and select a suitable repair mechanism.

In particular, it was revealed that MSH2-MSH3, a DNA mismatch repair protein, actually plays an important role in the DSB repair process. The researchers observed the recruitment of fluorescent protein-labeled MSH2-MSH3 proteins to the DSB site and revealed that this movement occurs via binding to a chromatin remodeling protein called SMARCAD1. MSH2-MSH3 binding to DSB facilitates recruitment of EXO1 (exonuclease 1) for long-term resection of damaged DNA.

After remote resection, damaged DNA is repaired via error-free HR. In addition, it was found that MSH2-MSH3 binding inhibited POLθ access, which mediates the more error-prone TMEJ pathway, thereby preventing mutations that might occur during DSB repair.

Director Myung said, “This study has revealed a novel function of the MSH2-MSH3 mismatch repair protein in regulating DSB repair,” adding, “The repair proteins that have been believed so far act independently in mismatch repair, double-stranded damage repair, and TMEJ repair pathways. it is now shown to interact closely with each other for maintenance of proper genomic integrity.

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




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