When cells in the human body divide, they must first make accurate copies of their DNA. This DNA replication process is one of the most important in all living organisms, but it is also fraught with risks of mutation, which can lead to cell death or cancer. Now, biologists have identified a multi-protein "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 and could inform the development of future treatments for neurologic and developmental disorders. The researchers, from the Perelman School of Medicine at the University of Pennsylvania and the University of Leeds, have found what appears to be a critical quality-control mechanism in cells.
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. While biologists know a good deal about how this process starts and proceeds, they have been puzzled by how replication is stopped or paused on the "lagging strand" of the DNA.
In the study, the researchers used advanced techniques, including cryo-electron microscopy and CRISPR-based mutation analyses, to identify a protein complex that has a central replication-stopping role for the lagging strand. This four-protein machine, which they call 55LCC, binds to DNA and its associated replication complex, and powered by two motor-like enzymes called ATPases, it appears to unfold the tightly folded replication complex, allowing it to be chopped up and cleared away.
The researchers suspect that 55LCC may be involved in regulating not just the DNA replication process associated with cell division, but also when DNA damaging lesions block replication. Inherited mutations in enzymes that help make up 55LCC are known to be associated with childhood syndromes involving hearing loss, cognitive and movement impairments, and epilepsy.