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Body and mind

The body’s cells build massive protein scaffolding around damaged DNA

New insights into the body’s repair mechanisms extend understanding of how DNA damage can lead to the development of various diseases, including cancer.

Researchers from the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen have discovered how cells build protein scaffolding around DNA damage.

The protein scaffolding is similar to putting a plaster cast on a broken arm, enabling healing without aggravating the damage.

The discovery is a basic research breakthrough that helps us better understand how DNA damage leads to diseases such as cancer. It also provides researchers with better opportunities to develop treatments for people whose cells cannot repair unstable DNA.

“This is a unique discovery of how the body’s natural defence mechanisms coordinate communication between proteins to repair damaged DNA. We can use this knowledge to obtain greater insight into genetic disorders and to design medicine to combat them,” explains a researcher behind the study, Jiri Lukas, Professor and Executive Director, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The study has been published in Nature.

DNA damaged continually

Cells’ DNA is continually damaged, and this can be harmful in several ways.

DNA contains the genetic recipe for how a cell should look and react, and missing pages in the recipe can make things go terribly wrong.

Damaged DNA can transform normal cells into cancer cells, wreck the immune response or cause the cells to die.

Since millions of cells in a human body divide every day, an advanced warning system is needed to constantly repair the damage caused by cell division errors, which may also result from environmental factors, including smoking and an unhealthy diet.

If these errors are not rectified, the DNA can be permanently damaged, with severe consequences.

Two proteins stabilize DNA breakage

Fortunately, the body’s cells are equipped with a whole arsenal of proteins that help to repair DNA damage.

Some of these proteins repair the damage itself, while others ensure that the damage does not worsen as it is being repaired. They create scaffolding around the DNA so it stays in place until it is fixed.

The researchers mapped the 53BP1 and RIF1proteins that comprise the scaffolding. The proteins create a three-dimensional structure around the DNA break, and the scaffolding then helps to stabilize the DNA and capture the proteins that will repair the damaged DNA.

“This is like putting a plaster cast around a broken arm to stabilize the fracture and prevent the damage from possibly getting so severe that it can no longer heal,” says the first author, Fena Ochs, Postdoctoral Fellow, Novo Nordisk Foundation Center for Protein Research.

Advanced microscopy to explore the cell nucleus

The researchers used an extremely advanced microscope that enabled them to see objects that are just one thousandth of the diameter of a human hair.

The researchers used this microscope to zoom into the cell nucleus and see in real time the processes going on around the damaged DNA, which is being actively repaired.

The researchers then saw very clearly how the protein scaffolding was assembled and developed around the DNA break.

Before this discovery, it was thought that protein scaffolding was created only immediately around the DNA damage, but Jiri Lukas and Fena Ochs’ research shows that the repair scaffold must be much larger. In other words, body’s cells play it totally safe when DNA is damaged.

They do much more than merely stabilize the DNA around the break. In fact, this is like erecting scaffolding throughout an entire city to repair one crack in the facade of one house.

“This emphasizes the importance of the cell stabilizing not only the DNA damage but also the surrounding environment so that it is disturbed as little as possible while the damage is repaired. In addition, the size of the scaffolding increases the likelihood of attracting the precious proteins in each cell that repair the damage, and that otherwise might be in short supply” says Jiri Lukas.

Cells need the help from the protein scaffolding

Jiri Lukas and Fena Ochs also investigated what happens when the scaffolding proteins do not function properly. They genetically disrupted the functioning of the proteins that makes the scaffold and recorded movies that captured how large parts of the damaged chromosome are falling apart.

Without the scaffolding proteins to shield the damaged DNA, the cells also attempted an alternative method to repair the damage. However, this often aggravated the damage instead by introducing mistakes to the healthy part of the genetic code.

“This may help to explain why people who lack the scaffolding proteins or have mutations are prone to developing diseases caused by unstable DNA: mostly cancer but also some related to the immune system, infertility, premature ageing and some types of neurodegeneration,” says Jiri Lukas.

Stabilization of chromatin topology safeguards genome integrity” has been published in Nature. Several of the authors are employed at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

Jiri Lukas
Group leader and Executive Director
Jiri Lukas is interested in how DNA repair and signaling proteins wire themselves into functional pathways, how are these pathways organized in the three-dimensional space of the cell nucleus, and how malfunction of these mechanisms impacts on etiology of cancer and other diseases marked by unstable genomes. His laboratory has contributed by major discoveries and concepts that illuminate physiology and pathology of genome surveillance. These discoveries include signaling pathways that delay cell cycle progression to DNA damage, role of regulatory ubiquitylation in orchestrating assembly of genome caretakers at damaged chromosomes, role of DNA replication stress in fueling genome instability during oncogenic transformation, and identification of rate-limiting genome caretakers as guardians of DNA repair fidelity and potentially druggable targets of cancer. Most recently, the Lukas lab became focused on investigating how DNA repair and signaling pathways operate in the context of endogenous and hence unavoidable genotoxic assaults such as fluctuations of cellular metabolic pathways. In addition to the conceptual focus, the Lukas lab is renowned for pioneering high-content imaging with genetic silencing and informatics to generate powerful data resources for studying genome caretaking proteins encoded by hitherto uncharacterized genes.