Researchers at the University of Copenhagen have identified a specific mechanism that protects cells against natural errors in DNA that could permanently damage the genetic code and lead to diseases such as cancer. The study has just been published in one of the most influential scientific journals, Nature Cell Biology.
Researchers at the University of Copenhagen have discovered a mechanism that gives human cells a chance to no longer accumulate mutations. This discovery could prove very useful for the development of new treatments against diseases caused by modifications of human DNA, such as cancer.
To limit the harmful modifications of the genetic code that can lead to potential diseases, cells rely on a natural defense mechanism. The new study shows that specialized proteins engulf and protect the damaged DNA and escort it until the damage can be repaired. The researchers found that this process relies on accurate timing and meticulous control inside the cells.
"We have discovered a specific mechanism in human cells that delays the spread of DNA damage in successive generations of dividing cells.This discovery helps us understand how our body protects itself from many types of cancer," says Professor Jiri Lukas, Head of Chromosome Stability and Dynamics Group and Executive Director of the Protein Research Center of the Novo Nordisk Foundation at the University of Copenhagen.
Defense against an inner enemy
Cancer usually develops from cells containing damaged DNA. It is well known that tobacco smoke or ultraviolet rays cause lung or skin cancer due to their ability to damage DNA. As bad as it may be, awareness of the origin of these cancers can result in reduced risk simply by stopping smoking or using sunscreen.
Normal cellular processes such as DNA replication are a more problematic cause of damage to DNA. These processes can not be avoided because they are inevitable whenever cells divide. The scale of this problem is better illustrated by realizing that our body consists of successive divisions of trillions of cells, all from a single fertilized egg. Every day, a quarter of a trillion cells in the adult human body continue to divide to replenish old or damaged tissue. Among the myriad of damage to DNA during each cell division process, the most dangerous are those that can be transmitted from the mother cells to the newly born daughter cells. These inherited DNA damage is the real "inner enemy" that can not be simply avoided by lifestyle changes.
Hereditary damage to DNA as a source of cancer
The new discovery is the result of many years of work and is rooted in the discovery made eight years ago by the same group (also published in Nature Cell Biology). In 2011, Jiri Lukas' group found that DNA damage caused by DNA replication problems is protected in specialized organelles called 53BP1 nuclear bodies.
In this new study, researchers used their ability to label 53BP1 nuclear bodies in living human cells using fluorescent dyes and then microscopically followed them for several successive generations. This allowed for the first time to observe the fate of inherited DNA damage directly from the moment of generation in the parent cells to their expression in the daughter cells. This was a real tour de force, because following live cells under the microscope for several hours, or even days, is a difficult task that only a few laboratories in the world can do.
Researchers have found that daughter cells are well-equipped to cope with life's challenges and mobilize 53BP1 nuclear bodies to "escort" hereditary genetic damage at a very advanced stage of their division cycle, when they become competent authorities for a last attempt to repair heritable genetic lesions.
The researchers also discovered that the key molecular component of this "toolbox for repair" is an enzyme called RAD52, which, thanks to this study, is now considered a true member of the family of tumor suppressor proteins that protects DNA against predisposing cancer. mutations.
"The 53BP1 nuclear bodies delay cell division in daughter cells in order to reach the only remaining time in their life cycle where they can repair the DNA damage that their mother caused but can not repair." This second chance is vital, as it is also the last one, have experimentally predicted and documented that a failure of this second chance converts the initially curable DNA damage into a damage that can no longer be repaired. The accumulation of such accidents could lead to illness, including cancer, "says Assistant Professor Kai John Neelsen of the Novo Nordisk Foundation Protein Research Center.
This knowledge can prove to be essential in improving cancer treatment. As many anticancer drugs damage the DNA of rapidly dividing cancer cells, it is essential to understand the timing and mechanisms of DNA repair to develop new drugs and minimize the side effects of treatments. current.
"Our work reveals unexpected ways in which cells treat damage inherited from DNA.With the identification of the key proteins at the root of this process, we laid the foundation for research on Potential therapeutic applications, "says postdoctoral researcher Julian Spies of the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen.
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Julian Spies et al., 53BP1 Nuclear Bodies Apply Replication Time to Under-replicated DNA to Limit Damage to Hereditary DNA. Nature Cell Biology (2019). DOI: 10.1038 / s41556-019-0293-6