Â鶹ÒùÔº

If DNA bridges persist between chromosomes during cell division, chromosomes are abnormally segregated, leading to genetic instability and cancer. Researchers at UNIST and IBS have experimentally revealed for the first time how a critical protein acts as a last resort to eliminate these dangerous DNA bridges, often cutting it close during the final moments of cell division.

Professor Anton Gartner (Distinguished Professor at the UNIST Graduate School of Medicine and Associate Faculty at the IBS Center of Genomic Integrity) and IBS Research Fellow Stephane Rolland have elucidated the molecular mechanism by which LEM-3 cuts DNA bridges during cytokinesis. Their study is in the journal Nucleic Acids Research.

Cell division is an essential biological process that removes aged cells and continuously renews tissues. In the human body, billions of cells divide each day: intestinal cells are completely renewed every 1–3 days, and skin cells approximately every 2–3 weeks.

During this process, DNA must be precisely duplicated and separated. However, incomplete DNA replication or chromosome entanglement can result in the formation of DNA bridges between two daughter cells. If these bridges are not properly resolved, it can lead to chromosomal instability, genetic information loss, and ultimately, cancer.

The team had previously found that LEM-3 plays a critical role in resolving persistent DNA bridges, acting as a last resort when other repair pathways fail. LEM-3 was specifically observed to localize to the midbody, the narrow structure that connects two daughter cells during the final stages of division. While most DNA bridges were removed even when other DNA repair factors were disrupted, the absence of LEM-3 led to persistent bridges and subsequent cell division failure.

LEM-3 is a nuclease, and nucleases act like a surgical knife on DNA. The team now investigated the reaction mechanism of LEM-3, which substrates are recognized and cut by LEM-3, and how the different domains of this nuclease contribute to its localization, catalytic activity, and DNA binding. Further, although LEM-3 serves as a vital guardian, the researchers discovered that it can also be hazardous if mislocalized.

LEM-3 must be tightly regulated and excluded from the nucleus. The team uncovered a toxic mutant that mislocalized to the nucleus, causing unintended DNA cleavage and ultimately embryonic lethality, highlighting the dangerous potential of unregulated LEM-3 activity.

The study was conducted using the model organism Caenorhabditis elegans, whose LEM-3 protein is evolutionarily conserved as ANKLE1 in humans.

Professor Anton Gartner said, "Given that ANKLE1 has been linked to the development of breast and colorectal cancers, our findings may contribute to the development of new strategies for cancer prevention and therapy."