The team behind a new study has discovered a novel mechanism for the protection of DNA. Their findings may influence future cancer treatments.
Why does DNA need protecting?
DNA is essential for life – it carries the instructions for all vital processes and functions. Therefore, it is not surprising that damage to DNA can have extremely serious consequences. Luckily, the majority of damage can be repaired by our cells. However, if damage is not repaired, gene function and regulation can become disrupted, which can subsequently lead to cancer and ageing.
As the name may suggest, a double-strand break (DSB) describes a type of DNA damage that leaves both strands of the DNA molecule broken. This can be caused by the by-products of metabolism, such as reactive oxygen species, or by environmental exposure to chemical agents. DSBs are particularly dangerous if not repaired. This is because they result in a free end of DNA which can then be bound by a different DNA molecule. This can subsequently lead to chromosomal translocation, which is an early step in cancer.
The protein 53BP1 has been known to promote the repair of DSBs. However, how exactly the protein worked and interacted with DNA was unclear until now. The team behind this recent study, published in Nature Communications, investigated 53BP1 in more detail.
53BP1 and heterochromatin
Firstly, the team created 53BP1 knockout cell lines and compared these to normal cell lines to try and discern the full range of 53BP1’s function. Imaging of these cells allowed the visualisation of 53BP1’s location in the nucleus.
The researchers found that 53BP1 accumulated at regions of heterochromatin. Further analysis revealed that 53BP1 molecules were wrapping around heterochromatin centres and co-localising with other proteins that support heterochromatin structure. Interestingly, the 53BP1 knockout cells had a large reduction in the number of heterochromatin centres. These results strongly suggest that 53BP1 has a previously unknown role in maintaining the structure of heterochromatin.
Mechanism for protecting DNA
Next, the team investigated the biological significance of 53BP1’s accumulation at heterochromatin. Amazingly, using live cell imaging, they found that 53BP1 formed small liquid droplets at heterochromatin centres. The droplet formation also required the presence of the protein HP1α, which is a component of heterochromatin. Together, the droplets of these two proteins stabilised heterochromatin structure.
Heterochromatin protects cells against genomic instability and cellular senescence. The team wanted to find out if 53BP1 droplets were involved in this protection. They discovered that 53BP1 knockout cells had much higher levels of DNA damage and instability. Cells which had mutated 53BP1 molecules also had higher levels of damage. Therefore, the team concluded that the liquid 53BP1 droplets protected cells from DNA damage at least partially through stabilising heterochromatin centres.
The protective role of 53BP1 discovered in this study is completely new and independent of its role in repairing DNA damage. The scientists hope that they can harness 53BP1’s role to help treat diseases that can arise from double-strand breaks, like cancer.
Senior author Youwei Zhang said:
“Our goal is to understand the molecular mechanisms that maintain the genome stability in human cells by identifying the genes and the signalling pathways involved. Long term, we hope to translate this knowledge into potential anticancer treatment strategies.”
Picture credit: Canva