by Huntsman Cancer Institute

To visualize LEM2’s role in mitosis, the Ullman Lab used colored
fluorescent markers to label the different components: LEM2, the
fibers, and the DNA. Credit: Huntsman Cancer Institute

To replace aging and worn cells, the body primarily uses a process
called mitosis, in which one cell divides into two. When a cell is
ready to divide, it duplicates its DNA so a complete copy is available
for each of the daughter cells. In this process, the DNA pieces, or
chromosomes, must be precisely apportioned into the daughter cells. If
one cell has an incomplete copy of the DNA or if the DNA becomes
damaged, genetic disorders and diseases such as cancer can result.

For cell division to occur, the two sets of DNA must be localized to
opposite sides of the cell. First, the compartment that normally
contains the DNA, the nucleus, disassembles its protective coating.
Then the chromosomes are separated by an apparatus of fibers. A new
nucleus forms around each DNA set. Finally, the cell splits into two,
each with its own re-formed nuclear compartment inside.

Scientists at Huntsman Cancer Institute (HCI) at the University of
Utah (U of U) and collaborators at the University of California, San
Francisco (UCSF) published research in the journal Natureextending our
understanding of the intricate process of cell division. They
discovered the protein LEM2 has two important functions during cell
division. First, LEM2 creates seals in the protective coating of
forming nuclei that keep the two sets of DNA shielded from damage.
Second, LEM2 recruits factors that disassemble the apparatus of fibers
responsible for separating the DNA sets. HCI’s Katharine Ullman,
Ph.D., and UCSF’s Adam Frost, Ph.D., collaborated over the last six
years on this work.

To visualize LEM2’s role in mitosis, the Ullman Lab used colored
fluorescent markers to label the different components: LEM2, the
fibers, and the DNA. This process allowed the team to film LEM2—from
when it first associates with intact fibers until the time of their
disassembly. They observed LEM2 proteins concentrating and forming a
gel-like seal with other proteins (ESCRTs) at holes where fibers
traverse the protective coat of the nucleus. This LEM2 “O-ring”
effectively sealed off the re-forming nuclear coat, safeguarding each
set of DNA from material surrounding the nucleus.

“Using our imaging methods, we were able to see a process that only
occurs over the course of about five minutes during cell division,
something that would have been very difficult to study otherwise,”
said Dollie LaJoie, Ph.D., a researcher in Ullman’s research group and
a co-author on the study.

“This work was strengthened by the fact that both teams worked on this
project using different approaches to better explain the role of
LEM2,” Ullman said. “My research group focused on this process in live
cells while Frost’s research group worked to understand more about the
protein itself.”

The authors note that this novel type of gel-like separation may prove
important for other critical cell functions that LEM2 participates in,
including higher-level DNA organization.

The authors also showed that disruptions to LEM2 as it assembles the
nucleus resulted in DNA damage—which jeopardizes normal cell function.

“This work opens a door to identifying new pathways for DNA to be
damaged, which in some cases may contribute to the development of
cancer,” said Ullman.

Moving forward, the Ullman and Frost Labs will build on this work by
investigating the connection between improper nucleus formation and
DNA damage. They will examine how cancer cells may lack the proper
regulation of both nuclear assembly and nuclear repair.

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Explore further

Nuclear membrane Lem2 necessary for nuclear scaling

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More information: Alexander von Appen et al, LEM2 phase separation
promotes ESCRT-mediated nuclear envelope reformation, Nature (2020).
DOI: 10.1038/s41586-020-2232-x
Journal information: Nature