Lamin C is important for keeping the genetic material of a cell tidy

In a study with mouse cells grown in the lab, researchers at Johns Hopkins Medicine say they have found that a protein that helps form a structural network beneath the surface of the cell’s “command center” – its nucleus – is essential. to ensure that the DNA inside stays tidy. The new experiments distinguish the role of the protein, called lamin C, revealing its utility in the diagnosis and treatment of a variety of genetic disorders related to DNA disorganization, such as the disease of rapid aging known as progeria, muscular dystrophy and cardiac disorders linked to mutations. in these proteins and related proteins.

“The impact of these findings could extend beyond known laminopathic diseases, as it appears that lamin C is important for the organization of the genome in general. We just don’t know at this point how lamin C behaves in other genome-disordered diseases, ”says Karen Reddy, Ph.D., assistant professor of biological chemistry at Johns University School of Medicine. Hopkins.

She continues: “A lot of people are familiar with the idea that genetic mutations – or errors in the genetic code – cause inherited diseases. However, highly disorganized genes could have as big an impact as mutations on the cause of the disease. “

Reddy notes that genetic testing generally does not take into account the organizational mechanisms of DNA, which can provide an important basis for understanding genetic diseases.

Reddy and his research team published the results of their study published on November 14 in Genome biology.

The nucleus of every human cell contains about 6 feet of tightly coiled DNA that contains the genetic instructions for every structure and function in the body. In order for the cell to continue to function, these strands of DNA must be organized into usable parts. Laminated proteins, which attach to the surface of the nucleus, do so by attaching themselves to segments of DNA, keeping them separate and tidy.

“Each compartment created by a laminate acts like a kitchen utensil drawer, keeping knives, forks and spoons within easy reach, and more rarely items used as serving pieces out of the way until you need it, ”says Reddy.

In an effort to better understand how lamins influence the way the cell uses and organizes its DNA, Reddy and his team used fluorescent dyes to track three types of protein lamins – A, B, and C – through cell division, when a cell’s DNA is duplicated and then split between two offspring cells.

While lamin B has been easily distinguished in previous studies, lamin A and lamin C have historically been treated as duplicate proteins because they are created from the same gene, says Reddy. However, there was growing evidence that type A and C lamins had distinct roles.

To sort them out, Reddy’s research team genetically engineered mouse embryonic cells to remove either the gene that creates lamin B or the gene that contains both A and C lamins. Then, the researchers used microscopes to observe the behaviors of the lamins and if the nuclear cells DNA remained organized while it divided.

The research team found that the nuclear DNA in cells lacking lamin B looked roughly like normal dividing cells, implying that lamin B may not be essential for DNA reorganization after cell division. However, nuclear DNA in cells lacking the A and C lamins did not reorganize cleanly, becoming tangled and unsorted from its normal compartments in the nucleus.

“It looked like there was a rowdy party in the normally well-organized kitchen,” says Reddy, cells devoid of lamins A and C. “Things were out of place and the DNA strands were active and inactive were interspersed and separated from the laminae at the edge of the nucleus.

Next, the researchers used a series of specialized chemical reagents to deactivate lamin A or lamin C in mouse cells, allowing them to test each protein independently.

Cells without lamin A appeared to be able to reorganize after cell division as efficiently as normal cells. However, the organization of nuclear DNA again fell into disarray in cells without lamin C.

Reddy says that a reason for this distinction has been revealed in the behavior of lamin C in dividing cells. His team found that while lamins A and B quickly bind to the surface of a newly formed nucleus and begin to grab sections of DNA, lamin C remains scattered throughout the nucleus and retains a special molecular tag called phosphorylation. Researchers believe this suggests that this modified C-lamin helps guide DNA into place during reorganization. Once DNA is organized, lamin C loses its molecular tag and associates with the rest of the lamins on the periphery of the nucleus.

“There’s this exquisite choreography of the different lamin proteins and DNA to get things as they should be,” says Reddy.

The results suggest that new tests could be developed to distinguish between lamins A and C and should be taken into account when screening for certain genetic diseases involving laminated proteins or other proteins at the periphery of the nucleus.

The gene that codes for lamins A and C is associated with inherited diseases that include three forms of muscular dystrophy: familial partial lipodystrophy, a condition that causes abnormal distribution of fat tissue; progeria; and several heart muscle disorders.

The researchers note that these results raise several new questions, including the role of lamins in the organization and regulation of DNA during development. The team hopes to identify how the protein lamins and the genome behave when a specific type of lamin is mutated or disrupted, as there appears to be an interaction between the different forms of lamins. They also plan to study the cellular pathways that control protein lamins, in particular for lamin C, in order to better distinguish the importance of its role in DNA control.

Reference: Wong X, Hoskins VE, Melendez-Perez AJ, Harr JC, Gordon M, Reddy KL. Lamin C is needed to establish the organization of the genome after mitosis. Biol genome. 2021; 22 (1): 305. do I: 10.1186 / s13059-021-02516-7

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