If cells’ recycling centres do not release acid and enzymes to the nucleus during cell division, cells cannot divide correctly. A researcher explains that this increases the risk of developing cancer and other diseases.
Research from the Danish Cancer Society Research Center shows that the molecular biology textbooks should be rewritten.
The lysosomes that function as the recycling centres of cells play a previously unknown and yet incredibly important role in cell division.
When a cell is ready to divide, the lysosomes move close to the cell nucleus and release a tiny quantity of acid and enzymes that cleaves the structural part of the DNA and catalyses cell division.
If the lysosomal enzymes are not applied to the chromatin during cell division, the DNA is not correctly replicated into the two new daughter cells, and then the cell dies or the risk of cancer increases.
This discovery may have profound consequences for understanding many cellular processes.
“This is perhaps most interesting in terms of basic research because the fact that lysosomes play this previously unknown role is totally surprising. We thought we knew pretty much everything about cell division, but it turns out that we did not. In addition, the lysosomes might play other roles that we have not yet investigated,” says a researcher behind the study, Marja Jäättelä, Professor and Unit Leader, Danish Cancer Society Research Center.
The discovery has been published in Nature Communications.
Lysosomes contain potent enzymes
Lysosomes could be called cells’ recycling centres because they digest and recycle waste inside the cells.
The lysosomes capture old proteins and organelles (cell structures that perform specific functions) and break these down into their constituents, including amino acids, so that the old material does not cause problems in the cells and the building blocks can be recycled to make new macromolecules.
To perform this important function, lysosomes are equipped with potent enzymes within the acid behind their tightly sealed membrane.
These enzymes are supposed to stay inside the membrane, because if they escape, they can cause problems inside the cells, cleaving many vital proteins and organelles into small fragments.
“All previous studies have shown that cells die if the lysosomes rupture. This assumption underlies all descriptions of lysosomal leakage, but it turns out to be false,” explains Marja Jäättelä.
Lysosomes may contain the key to curing cancer
Marja Jäättelä and her colleagues are interested in the lysosomes because, in addition to being the cells’ recycling centres, they also play a role in developing cancer.
The structure of lysosomes in cancer cells differs from that in normal cells. The membranes are more fragile, and the lysosomes use these more fragile membranes in forming metastases and invading other tissues.
Cancer researchers have therefore been interested in lysosomes for some time, and the idea is that puncturing the lysosomes in cancer cells can kill these cells in the body without damaging other cells.
“Puncturing the lysosomes in cancer cells kills them, and this makes them a very interesting therapeutic target,” says Marja Jäättelä.
Discovered new function by chance
The discovery of the new function of the lysosomes came as a surprise.
The researchers developed an advanced microscopy method to study the lysosomes.
They wanted to study what happens when the lysosomes leak. To enable this, they developed a highly sensitive galectin puncta assay, in which the galectin was bound to either an antibody or a fluorescent molecule.
Galectin has high affinity for binding to the inside of the lysosomal membrane, enabling the researchers to determine when the lysosomes were leaking and galectin entered.
“This is the first time we have been able to study the damaged lysosomes with such precision,” explains Marja Jäättelä.
Lysosomal enzymes cleave the chromatin structure
When the researchers examined the lysosomes using their newly developed method, they were surprised to discover that the lysosomes released enzymes and applied them locally for cell division.
“We have also assumed that the enzymes function only in the highly acidic environment inside the lysosomes, but our results show that they can also briefly retain their activity in the neutral pH of the cell. Other studies have shown that they can maintain this activity for 15 to 30 minutes,” says Marja Jäättelä.
Marja Jäättelä and her colleagues found that the release of enzymes was associated with cell division. However, when they manipulated the lysosomes to not release the enzymes, this inhibited cell division.
More specifically, the enzymes play a role in cleaving histone H3, a structural molecule that binds DNA sequences throughout the cell cycle. If histone H3 is not cleaved into fragments, the DNA is not segregated and cell division cannot be completed correctly.
“We now have a whole new understanding of what happens when cells divide. This may be important for research into numerous diseases, including cancer, which may be caused by errors in the segregation of DNA, and diseases of the nervous system caused by defects in the cells’ lysosomes,” says Marja Jäättelä.
Links between high cholesterol, lysosomes and developing cancer
Marja Jäättelä explains another interesting perspective that the researchers will examine in the future.
People with a high cholesterol level have more stable lysosomal membranes, and this may limit the ability of the lysosomes to release the life-giving enzymes.
Marja Jäättelä therefore imagines that this may be one of the mechanisms that links high cholesterol with cancer.
“Surprisingly, the cells allow such dangerous enzymes to come very close to the cell nucleus, one of the most sensitive areas in a cell. This must be very tightly regulated to prevent errors. This regulation and the link between cholesterol and the risk of developing cancer is what we will focus on now,” says Marja Jäättelä.
“Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation” has been published in Nature Communications. In 2015, the Novo Nordisk Foundation awarded a grant to Marja Jäättelä for the project How Do Cells Maintain Lysosomal Membrane Integrity?