Each of the body's millions of cells contains an exact copy of our DNA. This places great demands on the machinery that replicates the DNA when cells divide. If things go wrong serious diseases such as cancer can emerge. Now scientists have found what seems to be the final chance for cell division that may prevent daughter cells from inheriting permanent DNA errors from the mother cell. The new finding provides important knowledge on what can go wrong when cancer develops and reveals an important Achilles heel in cancer cells.
Damage to our genes is a frequent cause of cancer. This damage eliminates the cells’ ability to stop dividing. Researchers already know a lot about how tobacco smoke and ultraviolet radiation damage our DNA and lead to lung or skin cancer, but they know very little about how cancer can develop naturally from errors in the continual cell division in the human body.
“These errors occur all the time when the body replicates its DNA through cell division. We have now discovered how the body ensures that this type of DNA error is not propagated. During replication, the cell engulfs and protects the damaged DNA while simultaneously restraining replication. The new knowledge of how cells prevent damage to the genetic code may be crucial for improving existing treatments and developing new treatments against cancer,” explains Kai John Neelsen, senior scientist in Jiri Lukas’ group at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.
Cell division on standby
The new finding builds on a discovery 8 years ago when Jiri Lukas and his group found that our tissues defend against errors during cell division through highly specialized organelles (structures) within the cell nuclei: 53BP1 (p53 binding protein 1) nuclear bodies. Despite small in size, these organelles control the cells’ growth rate and play a significant role when the cells divide.
“It all started when we observed 53BP1 nuclear bodies as peculiar globular structures that often emerged right after cell division in the newly born daughter cells. We did not understand the purpose of this phenomenon, but since then we have followed the 53BP1 nuclear bodies during cell division by marking them with fluorescent dyes and observing with microscopes in living cells. When the daughter cell is born, the special protein structure containing the 53BP1 protein immediately engulfs any DNA damage inherited from the mother cells and sets in motion a series of events whose ultimate goal is to mend the damage and thus stop its propagation to the next generation of cells.”
The 53BP1 nuclear body in the daughter cell thus gives the body an extra and last chance to repair the damaged DNA that the mother cell could not repair itself. In addition to identifying and engulfing the DNA errors, the cell machinery does another remarkable thing: putting cell division on standby, so the error can be corrected, and the researchers found out how in the new study.
“The 53BP1 nuclear body restrains and adjusts the replication timing process so that the proteins can repair the DNA lesions at exactly the right time. It gradually becomes smaller and disappears at exactly at the time when the cells are ready to repair the damage. We have also shown that, if this last chance fails, the error can no longer be corrected and will probably lead to serious diseases, including cancer,” summarizes Julian Spies, first author.
Improving existing cancer treatments
The repair protein in the cells thus has extra time to repair the errors in the genetic code, and the researchers have now also found the RAD52 enzyme that actually carries out the repair. According to the researchers, RAD52 should now be included as a key component of the arsenal of tumour-suppressing proteins that can be used in fighting cancer.
“It may seem somewhat strange that RAD52, which is actually repairing cells, can be a target for cancer treatment. However, remember that cancer cells divide more rapidly and therefore need RAD52 more than other cells. So, if you can suppress RAD52, you can strike cancer cells with extra impact.”
The researchers do not yet know enough about RAD52 and how it is regulated. If they find this out, they hope to be able to build a solid platform for developing both better and completely new drugs. The new discovery therefore greatly improves the understanding of how the body protects itself against many forms of cancer. This may be crucial for improving existing cancer treatments.
“An adult’s body contains trillions of cells. Every day, a quarter of a trillion cells divide to rebuild or renew damaged or old tissue. Our findings provide better understanding of the natural timing of cell division and how the body defends against DNA damage and mutations. Using this knowledge, we can now begin to minimize the side-effects of current cancer treatments”, explains Jiri Lukas his team’s effort.
“53BP1 nuclear bodies enforce replication timing at under-replicated DNA to limit heritable DNA damage” has been published in Nature Cell Biology. The research was carried out at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.