Nature sub-journal identifies new mechanism to protect DNA

The discovery, involving the protein 53BP1, provides insight into how cells maintain the integrity of DNA in the nucleus, which is critical for preventing diseases such as premature aging and cancer

The study was conducted by a research team led by Youwei Zhang, an associate professor of pharmacology at Case Western Reserve School of Medicine and a member of the Molecular Oncology Program at the Case Comprehensive Cancer Center

DNA, or deoxyribonucleic acid, is the chemical name for the molecule that carries genetic instructions in all living things

53BP1 is a large protein that determines how cells repair a specific type of DNA damage - a DNA double-strand break (DSB), in which both DNA strands break, leaving free DNA ends floating in the nucleus of the cell

When DSBs occur, if not repaired, DNA ends can fuse where they should not normally be fused, resulting in the destruction of genetic information

In this study, the team found that 53BP1 has a biological function to regulate DNA structure, particularly in a highly compact region called heterochromatin

The researchers found that this new function involves the activity of a new form of 53BP1, in which the protein aggregates and forms small droplets in regions of condensed DNA -- a process known as liquid-liquid phase separation, similar to that found in salad dressings.

The team determined how 53BP1 forms droplets: they found that this process requires the participation of other known proteins to support the structure of these highly concentrated DNAs

They then performed a detailed molecular analysis to break down the large protein into smaller pieces and determine which fragments are critical for 53BP1's droplet formation

"What's more exciting is that through these comprehensive analyses, we found that this novel protective activity of 53BP1 is independent of the protein's broad role in repairing DNA damage, suggesting that 53BP1 has an entirely new function," Zhang said

Armed with this new information, Zhang and his team hope to better understand how diseases such as cancer are prevented, and even devise therapies that exploit the novel properties of 53BP1 to treat cancer

Professor Zhang's lab is focused on understanding cell biology to develop anti-cancer therapies—specifically how cells protect DNA stability

"Our goal," Zhang said, "is to understand the molecular mechanisms that maintain genomic stability in human cells by identifying genes and associated signaling pathways

Journal Reference :

1. Lei Zhang, Xinran Geng, Fangfang Wang, Jinshan Tang, Yu Ichida, Arishya Sharma, Sora Jin, Mingyue Chen, Mingliang Tang, Franklin Mayca Pozo, Wenxiu Wang, Janet Wang, Michal Wozniak, Xiaoxia Guo, Masaru Miyagi, Fulai Jin, Yongjie Xu, Xinsheng Yao, Youwei Zhang.