How Cells Relieve DNA Replication Stress

Scientists in South Korea have identified a mechanism by which mammalian cells prevent DNA replication from stalling due to internal or external stressors.

AsianScientist (Feb. 10, 2020) – A research group in South Korea has discovered a molecular pathway involved in regulating DNA replication during cell division. The findings, which have implications for the development and progression of cancer, are published in the journal Nature Communications.

DNA stores all of the information necessary for life phenomena, and a cell transmits its own genetic information to two daughter cells through DNA replication and cell division. Replication stress can be caused by extracellular and intracellular sources during DNA replication, which leads to slowed or stalled replication.

If cells do not properly cope with such risks, chromosome break and rearrangement will occur, resulting in genomic instability. That helps explain why replication stress is one of the major contributors to cancer development. Although many DNA repair proteins function to protect and restart stalled replication processes under stress conditions, it is still unclear how replisome proteins, which are real players in DNA replication, contribute and communicate with those proteins to ensure faithful DNA replication.

Led by Professor Myung Kyungjae and Dr. Lee Kyoo-young at the Institute of Basic Science, South Korea, researchers have identified a protein called ATAD5 that actively deals with replication stress. Although ATAD5 has been known as a tumor suppressor by maintaining genomic stability and suppressing tumorigenesis, it was unclear whether the replication regulatory protein is also involved in the replication stress response.

In the study, the scientists demonstrated that ATAD5-depleted cells show characteristic features of replication stress such as a slow replication rate. They found that, when ATAD5 level is reduced, cells cannot resume DNA replication stalled by replication stress, and this was associated with increases in genome instability.

Further experiments showed that ATAD5 promotes the recruitment of another protein named RAD51 to stalled replication sites by direct protein-protein interaction. RAD51 RAD51 then wraps around the DNA to stabilize its DNA structure, which eventually allows DNA replication to resume.

“We have identified the fundamental mechanism of replication stress control, which is a major [factor in] cancer. Hopefully our work will contribute to the development of cancer therapy,” explains director Myung.

Lee added that the team intends to examine how intracellular factors may contribute to replication stress and how cells selectively recognize and cope with different stressors.

The article can be found at: Park et al. (2019) ATAD5 Promotes Replication Restart by Regulating RAD51 and PCNA in Response to Replication Stress.


Source: Institute for Basic Science; Photo: Shutterstock.
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