Researchers from the University of Copenhagen have discovered a mechanism that gives human cells a chance to stop piling up mutations when cells replicate and divide in the body. The discovery could prove to be very useful in the development of new treatments against diseases caused by changes in human DNA such as cancer.
Fact Box
The human body consists of billions of cells which continuously renew themselves through cell division, also known as DNA replication. All cells in the body hold genetic information that determines how new cells are formed. However, if the genetic material has been damaged, a cell may mutate and develop into cancer.
To limit harmful changes in the genetic code that may lead to potential diseases, the cells in our body rely on a natural defense mechanism. The new study shows how specialised 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.
‘We have discovered a specific mechanism in human cells that delay propagation of DNA damage in successive generations of dividing cells. This discovery helps us understand how our bodies protect themselves from many types of cancer’, says Professor Jiri Lukas, Head of the Chromosome Stability and Dynamics Group and Executive Director of the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen.
Specialised proteins protect damaged DNA in the cell nucleus (pink shapes) until the damage can be repaired.
Defense against an enemy within
Cancer typically develops from cells with damaged DNA. It is well-known that tobacco smoke or ultraviolet light causes lung or skin cancer precisely due to their ability to damage DNA. However bad this may be, the hope in these environment-caused cancers is that we are aware of their origins and can thus dramatically reduce the risk simply by discarding cigarettes or shielding ourselves against excessive exposure to sunlight.
What is less known is that a more problematic source of DNA damage is normal cellular processes such as DNA replication. These cannot be avoided because they are inevitably in action every time cells divide. The scale of this problem is best illustrated by realizing that our bodies are made up by successive divisions of trillions of cells, all originating 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. Amongst the multitude of DNA damage incurred during each such cell division process, the most dangerous are those that can be passed on from mother cells to newly born daughter cells. This inherited DNA damage is the true ‘enemy within’ that cannot be simply avoided by changing one’s lifestyle.
Fact box
A mother cell is one which divides to give rise to two daughter cells. Daughter cells are genetically identical to the parent cell because they contain the same number and type of chromosomes.
Now, researchers from the University of Copenhagen have identified a process that counteracts the accumulation of inherited DNA damage. The discovery reveals that our bodies are naturally equipped with the means to actively fight against propagating cancer-promoting mutations every time a cell is born.
Heritable DNA damage as a source of cancer
The new discovery is a result of many years of work and is rooted in the finding made eight years ago by the same group (also published in Nature Cell Biology). In 2011, Jiri Lukas’ group found that inherited DNA damage caused by problems during DNA replication is protected in specialised organelles (literally ‘small organs’; in practice sub-cellular compartments with a specific function) called ‘53BP1 nuclear bodies.
In the new study, 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 researchers found that daughter cells are well equipped for the challenges of life and mobilise 53BP1 nuclear bodies to ‘escort’ the inherited DNA lesions to a very late stage of their division cycle when they become competent for one last attempt to repair inherited DNA lesions.
Illustration (click to enlarge): A mother cell suffers from a problem during DNA replication (small star). The daughter cell inherits the DNA damage and forms a 53BP1 nuclear body (pink spot) around it immediately after its birth. The 53BP1 nuclear body ‘escorts’ the inherited DNA lesion until the repair can take place (check mark).
The researchers also found that the key molecular part of this ‘repair toolkit’ is an enzyme called RAD52, which as a result of this study now qualifies as a true member of the tumour 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”, says Assistant Professor Kai John Neelsen 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 minimising the side effects of current treatments.
“Our work reveals unexpected ways in which cells deal with inherited DNA damage. With the identification of the key proteins driving this process, we have laid the foundation for investigations into potential therapeutic applications”, says Postdoc Julian Spies of the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen.
Source: https://healthscienc...lead-to-cancer/
Original source: https://www.nature.c...1556-019-0293-6
