DNA double-strand breaks (DSB) are particularly troublesome because they can lead to cell death if not repaired. And, if not repaired correctly, DSBs can cause deletions, translocations, and fusions in the DNA.
The protein called 53BP1 is primarily known as a critical player in regulating DNA double-strand break (DSB) repair choice. However, its involvement in other biological processes is less well understood.
Scientists from the Case Western Reserve University have found that the same protein also protects the integrity of DNA by preserving its structural shape. Specifically, the protein 53BP1 has a biological function in mediating the structure of DNA, particularly at a highly compacted region called heterochromatin.
The protein has a new form of activity in this biological function. It accumulates at the condensed DNA regions and forms small liquid droplets.
The formation of liquid droplets involves the participation of other proteins known to support the structure of that highly condensed DNA. But, scientists discovered that 53BP1 stabilizes the cluster of these proteins at these DNA regions, which is essential for keeping the overall function of the DNA.
Scientists further conducted a detailed molecular analysis to break the large protein into small pieces. Through this, they determined which pieces are essential for the liquid droplet formation of 53BP1. They further changed the amino acid of a specific position of the 53BP1 protein and determined the contribution of several critical amino acids for this new function.
Youwei Zhang, an associate professor of pharmacology at the Case Western Reserve School of Medicine, said, “More excitingly, through these comprehensive analyses, we found that this new protective activity of 53BP1 is independent of the widely known role of this protein in repairing DNA damage, indicating a new function of 53BP1. Our study suggests that, in addition to DSB repair modulation, 53BP1 contributes to the maintenance of genome stability through the formation of these liquid droplets.”
The study could help scientists understand how diseases like cancer can be prevented. It can also help them design therapies that use this new feature of 53BP1 to treat cancers in the future.
- Zhang, L., Geng, X., Wang, F. et al. 53BP1 regulates heterochromatin through liquid phase separation. Nat Commun 13, 360 (2022). DOI: 10.1038/s41467-022-28019-y