When a mother cells leaves a daughter cell a dubious bequest—under-replicated and lesion-prone DNA—it may propagate through subsequent generations of dividing cells, giving rise to cancer. To prevent inherited DNA damage from culminating in disease, a daughter cell has one last chance to put right what went wrong in the generation before. By sequestering under-replicated DNA in a subcellular compartment, the daughter cell delays replication of the faulty DNA, which may, in the meantime, undergo repair.
This delicate repair process has been tracked by scientists based at the University of Copenhagen and led by Jiri Lukas, professor and executive director of the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen. In a new study, the scientists show how specialized proteins engulf and protect the damaged DNA and “escort” it until the damage can be repaired. The researchers discovered that this process relies on precise timing and meticulous control inside the cells.
The new discovery is a result of many years of work and is rooted in the finding made eight years ago by Lukas’ group. In 2011, the group found that inherited DNA damage caused by problems during DNA replication is protected in specialized organelles called 53BP1 nuclear bodies.
In the new study (“53BP1 nuclear bodies enforce replication timing at under-replicated DNA to limit heritable DNA damage”), which appeared recently in the journal Nature Cell Biology, the researchers took advantage of their ability to label the 53BP1 nuclear bodies in living human cells using fluorescent dyes and then followed them under the microscope over several successive generations. This made it possible for the first time to observe the fate of inherited DNA damage directly from the time of generation in mother cells to their final destiny in daughter cells. It was a true tour-de-force, as tracking living cells under the microscope for many hours, even days is a very challenging task, which only a few laboratories in the world can do.
“The formation of 53BP1-NBs interrupts the chain of iterative damage intrinsically embedded in under-replicated DNA,” the authors of the new study wrote. “Unlike clastogen-induced 53BP1 foci that are repaired throughout interphase, 53BP1-NBs restrain replication of the embedded genomic loci until late S phase, thus enabling the dedicated RAD52-mediated repair of UR-DNA lesions.”
These findings suggest that the enzyme called RAD52 now qualifies as a true member of the tumor suppressor family of proteins that guards our DNA against cancer-predisposing mutations.
“53BP1 nuclear bodies delay cell division in daughter cells in order to reach the only remaining time in their lifecycle when they can mend DNA lesions that their mother caused but could not fix. This second chance is vital because it is also the last one. We have predicted and then experimentally documented that a failure of this second chance converts the initially curable DNA damage to one that can no longer be fixed. Accumulation of such mishaps could lead to disease, including cancer,” said Kai John Neelsen, a study co-author and assistant professor of the Novo Nordisk Foundation Center for Protein Research.
This knowledge may prove vital in the improvement of cancer therapy. As many cancer drugs damage the DNA of rapidly dividing cancer cells, understanding the timing and mechanisms for repairing DNA is essential in developing new drugs and minimizing the side effects of current treatments.
“Through adjusting replication timing and repair pathway choice at under-replicated loci,” the article’s authors concluded, “53BP1-NBs enable the completion of genome duplication of inherited under-replicated DNA and prevent the conversion of stochastic under-replications into genome instability.”