Roles and Mechanisms of LEM-3 Protein Domains in Preventing Abnormal Cell Division
LEM-3 Outside the Cytoplasm Is Lethal to Organisms... Published in Nucleic Acids Research
If DNA bridges are not eliminated during cell division, chromosomes may be abnormally segregated, leading to genetic issues such as cancer. For the first time, the mechanism of a protein that serves as the final safeguard against this problem has been revealed through experiments conducted by research teams at UNIST and the Institute for Basic Science (IBS).
On May 20, a team led by Anton Gartner, Distinguished Professor at the UNIST Graduate School of Medical Science, and Stephane Rolland, IBS Research Fellow, announced that they have elucidated at the molecular level how the LEM-3 protein, which severs DNA bridges remaining between chromosomes during cell division, operates.
Research team (from top left clockwise): Anton Gartner Distinguished Professor, Stephan Rolland IBS Research Fellow (currently Associate Professor at UNIST), Kadisha Salemova Researcher, Peter Geary Researcher (first author). Provided by UNIST
Cell division is the process by which aged cells are removed and new cells are created. In the human body, billions of cells divide each day, with the intestine being renewed in just 1 to 3 days, and the skin in 2 to 3 weeks.
During division, genetic material (DNA) is replicated. If replication is incomplete or chromosomes are not properly separated, a connecting structure called a "DNA bridge" remains between the two newly formed daughter cells. Failure to properly resolve this bridge can result in chromosomal abnormalities and loss of genetic information, and in severe cases, may lead to cancer.
The research team’s previous studies found that the LEM-3 protein acts as the last resort for removing DNA bridges during the late stages of cell division. LEM-3 was observed to be located in the midbody, a narrow structure connecting the two daughter cells at the final stage of division. If LEM-3 is deficient, DNA bridges persist even in the presence of other DNA repair factors, resulting in failed cell division. However, the precise mechanism of LEM-3 action had not been clarified until now.
According to this study, the LEM-like domain of this protein recognizes DNA bridges and ensures the accurate localization of LEM-3 to the midbody, while the GIY-YIG domain is responsible for directly cutting the bridges.
When a mutation was introduced into the LEM-like domain, which acts as a guide, the LEM-3 protein was mislocalized into the nucleus instead of remaining in the cytoplasm. As a result, DNA stored in the nucleus was inadvertently cleaved, leading to embryonic death during development.
Stephane Rolland explained, "LEM-3 normally resides in the cytoplasm, serving as the 'final resolver' to prevent abnormal cell division. However, if it is mislocalized, it becomes a threat to the cell itself?much like a surgeon's scalpel in the wrong place."
The research was conducted using the model organism Caenorhabditis elegans, and the LEM-3 protein in this organism is conserved in humans as a similar protein called ANKLE1.
Anton Gartner stated, "ANKLE1 is known as a gene associated with the development of certain cancers, including breast and colorectal cancer. This discovery is expected to contribute to the development of strategies for cancer prevention and treatment."
The research findings were published in the international journal Nucleic Acids Research on April 11.
This research was supported by the National Research Foundation of Korea under the Ministry of Science and ICT, the Institute for Basic Science (IBS), and the UK Biotechnology and Biological Sciences Research Council (BBSRC).
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