One more step toward understanding how cells repair their own DNA
Unrepaired DNA can cause serious diseases, including cancer. In a recent study, scientists from Chung-Ang University discovered an important pathway that regulates DNA damage repair. They showed that methylation of a major DNA repair protein is critical to cell survival after DNA damage and identified two other proteins involved in this process. This novel discovery could help us understand how abnormal DNA damage repair is involved in the occurrence of various diseases, including cancer.
DNA is a molecule that carries important genetic information—and thus, it is no surprise that its maintenance and repair are crucial for proper cellular function and survival. Multiple proteins are involved in ensuring that the DNA is repaired correctly. One such protein is UHRF1, but currently, very little is known about how its activity is regulated. If anything goes wrong with proteins involved in DNA damage repair, it can lead to severe diseases, including cancer. Thus, understanding the role and function in detail can provide useful information about how certain diseases can be treated.
In a study published in Nucleic Acids Research, scientists from Chung-Ang University, Korea wanted to find out more about UHRF1 and how it is “regulated” or controlled. Prof Sang-Beom Seo, the study’s lead researcher says, “Previous work has shown that some proteins are important regulators of DNA damage repair, but there wasn’t any objective evidence directly linking them with UHRF1. Thus, we wanted to focus on these proteins that might play a role in UHRF1 activity.”
To begin with, Prof Seo and his team focused on a protein called SET7, which is known to activate various other proteins involved in the DNA damage response. This made the scientists wonder: could SET7 be involved in regulating UHRF1 too? To find out, the researchers performed multiple experiments to see the effect of SET7 on UHRF1—both in vitro (in test tubes) and in vivo (in actual cells). Both tests confirmed SET7’s effect on UHRF1: it influenced the activity of UHRF1 by adding methyl groups to its structure. Not only this—they even managed to show the exact sites at which the methyl groups were added: in the 370-685 amino acid region. The scientists also knew that to maintain proper balance in cells, methylation must be offset by regular demethylation (removal of methyl groups). And thus, they went on to perform experiments to identify the protein that demethylates UHRF1 after methylation by SET7. They successfully found and verified a protein called LSD1 as the mediator of UHRF1 demethylation. Prof Seo explains, “Our data showed that SET7 and LSD1 tightly regulate the process of DNA repair through UHRF1 action. This was unprecedented: before, it was thought that UHRF1 was only involved in methylation during cell division.”
Encouraged by these findings, the researchers wanted to pinpoint exactly when this DNA repair pathway occurs in the life cycle of a cell. Through further analyses, they showed that during the cell’s S phase (when DNA replication happens and the chance of DNA breakage is higher), UHRF1 must undergo a process called phosphorylation, in which phosphate groups are added to its structure. This changes the enzyme’s structure and allows it to be methylated by SET7. The methylated UHRF1 then activates a protein called PCNA to start DNA repair. Once the repair is complete, LSD1 demethylates UHRF1, and this ends the pathway. Explaining these findings, Prof Seo says, “This is an exquisite and finely tuned mechanism, with methylation playing a central role in the pathway.”
This study is crucial in expanding our current knowledge of DNA damage repair. Prof Seo concludes, “A number of studies have reported on the progression of cancer caused by DNA damage. For example, women with mutations in BRCA, one of the DNA repair proteins, have a 60-80% risk of breast cancer and a 40% risk of ovarian cancer. Therefore, understanding the process of DNA damage repair is essential to eliminate the causes of various cancers and to suggest effective treatment methods.”
Indeed, this study brings us one more step closer toward understanding how DNA damage repair happens and how this newly acquired understanding can be used to treat various diseases.
Title of original paper: Methylation of UHRF1 by SET7 is essential for DNA double-strand break repair
Name of author: Prof Sang-Beom Seo
Affiliation: Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 06974, Republic of Korea
About Chung-Ang University
Chung-Ang University is a private comprehensive research university located in Seoul, South Korea. It was started as a kindergarten in 1918 and attained university status in 1953. It is fully accredited by the Ministry of Education of Korea. Chung-Ang University conducts research activities under the slogan of “Justice and Truth.” Its new vision for completing 100 years is “The Global Creative Leader.” Chung-Ang University offers undergraduate, postgraduate, and doctoral programs, which encompass a law school, management program, and medical school; it has 16 undergraduate and graduate schools each. Chung-Ang University’s culture and arts programs are considered the best in Korea.
About Professor Seo from Chung-Ang University
Dr. Sang-Beom Seo is a Professor at the Department of Life Science in the College of Natural Sciences, Chung-Ang University, Korea. He is also the lead author of this study. He received his PhD degree from State University of New York, Binghamton, and went on to pursue his post-doctoral research at the University of Pennsylvania School of Medicine. He has more than 67 research publications to his credit. His main research interests include epigenetics, cell biology, and chromatin biology.
Jin hwan Kim