Humans and baker’s yeast share more similarities than we might think, particularly in a crucial process that ensures DNA is accurately copied, according to two recent studies. These studies present the first visualization of a molecular complex known as CTF18-RFC in humans and Ctf18-RFC in yeast. This complex is responsible for loading a “clamp” onto DNA, preventing components of the replication machinery from detaching from the DNA strand.
Humans and baker’s yeast share some surprising similarities, especially an essential mechanism that ensures accurate DNA replication, as indicated by two studies released in the journals Science and Proceedings of the National Academy of Sciences.
The research vividly illustrates, for the first time, a molecular complex—CTF18-RFC in humans and Ctf18-RFC in yeast—responsible for placing a “clamp” onto DNA to prevent essential replication components from becoming dislodged.
This discovery stems from the work of long-term collaborators Huilin Li, Ph.D., from Van Andel Institute, and Michael O’Donnell, Ph.D., from The Rockefeller University, who are exploring the complex mechanisms that allow genetic information to be accurately passed down through generations of cells.
“Accurate DNA copying is vital for the continuation of life,” Li stated. “Our research contributes crucial insights into DNA replication, which may enhance the understanding of health issues related to DNA replication.”
DNA replication is a meticulously regulated process that duplicates the genetic blueprint, facilitating the transfer of its instructions from one generation of cells to the next. In conditions like cancer, these mechanisms can fail, leading to erratic or improper DNA duplication with serious implications.
To date, over 40 diseases, including various cancers and some rare disorders, have been associated with issues arising from DNA replication.
The replication process starts with the unwinding of DNA’s double-helix structure, creating two strands referred to as the leading and lagging strands. A group of molecules then works to fill in the missing segments, transforming a single DNA helix into two copies. A significant part of this task is handled by enzymes known as polymerases, which construct the essential components of DNA.
However, polymerases on their own struggle to remain attached to the DNA strand. They depend on CTF18-RFC in humans and Ctf18-RFC in yeast to place a ring-shaped clamp onto the leading strand, while another clamp loader, RFC, performs a similar role on the lagging strand. Once attached, the clamp closes and signals the polymerases to begin the DNA replication process.
Employing advanced cryo-electron microscopy, Li, O’Donnell, and their teams uncovered new details about the structures of the leading strand clamp loaders, including a “hook” that triggers the leading strand polymerase to release the new DNA strand for recognition by the clamp loader. This differentiation illustrates a significant functional distinction between the leading strand clamp loader (CTF18-RFC) and the lagging strand clamp loader (RFC), shedding light on the different DNA replication processes occurring on the two strands.
Finally, the research revealed common characteristics shared by the yeast and human leading strand clamp loaders, highlighting an evolutionary connection between the two. This finding underscores the importance of yeast as effective yet simple models for genetic research.
Additional contributors to the Proceedings of the National Academy of Sciences paper include Qing He, Ph.D., and Feng Wang, Ph.D., from VAI. Other authors of the Science paper include Zuanning Yuan, Ph.D., from VAI, along with Roxana Georgescu, Ph.D., Nina Y. Yao, Ph.D., and Olga Yurieva, Ph.D., from The Rockefeller University.
