When cells in the human body divide, they must first make accurate copies of their DNA. The DNA replication exercise is one of the most important processes in all living organisms and is fraught with risks of mutation, which can lead to cell death or cancer. Now, findings from biologists from the Perelman School of Medicine and from the University of Leeds have identified a multiprotein “machine” in cells that helps govern the pausing or stopping of DNA replication to ensure its smooth progress.
The discovery, published in Cell, advances the understanding of DNA replication, helps explain a puzzling set of genetic diseases, and could inform the development of future treatments for neurologic and developmental disorders.
“We’ve found what appears to be a critical quality-control mechanism in cells,” says senior co-corresponding author Roger Greenberg, the J. Samuel Staub, M.D. Professor in the department of Cancer Biology, director of the Penn Center for Genome Integrity, and director of basic science at the Basser Center for BRCA at Penn Medicine. “Trillions of cells in our body divide every single day, and this requires accurate replication of our genomes. Our work describes a new mechanism that regulates protein stability in replicating DNA. We now know a bit more about an important step in this complex biological process.”
The DNA replication process is carried out by multiple protein complexes with highly specialized functions, including the unwinding of DNA and the copying of the two unwound DNA strands. The process is akin to a factory assembly line where balls made up of massive, crumpled strings of data are unraveled, allowing specific pieces to be trimmed and copied. Biologists know a good deal about how this process starts and proceeds, but know less about how it is stopped or paused.
Prior studies have identified proteins that stop replication along one DNA strand—the “leading strand”—by inducing the disassembly and recycling of DNA-replication components on that strand. How replication is stopped on the other strand—the “lagging strand”—has been a mystery.
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