Humans and baker’s yeast have more in common than meets the eye, including an important mechanism that helps ensure DNA is copied correctly, reports a pair of studies published in the journals Science and Proceedings of the National Academy of Sciences.
The findings visualize for the first
time a molecular complex — called CTF18-RFC in humans and Ctf18-RFC in yeast —
that loads a “clamp” onto DNA to keep parts of the replication machinery from
falling off the DNA strand.
It is the latest discovery from longtime
collaborators Huilin Li, Ph.D., of Van Andel Institute, and Michael O’Donnell,
Ph.D., of The Rockefeller
University, to shed light
on the intricate mechanisms that enable the faithful passage of genetic
information from generation to generation of cells.
“The accurate copying of DNA is
fundamental to the propagation of life,” Li said. “Our findings add key pieces
to the puzzle of DNA replication and could improve understanding of DNA
replication-related health conditions.”
DNA replication is a tightly controlled
process that copies the genetic code, allowing its instructions to be conveyed
from one generation of cells to the next. In diseases like cancer, these
mechanisms can fail, leading to uncontrolled or faulty replication with
devastating consequences.
To date, at least 40 diseases, including many cancers and rare disorders, have been linked to problems with DNA replication.
DNA
replication is a complex process with many moving parts. In humans, the
molecular complex CTF18-RFC, pictured above, keeps parts of the replication
machinery from falling off the DNA strand. Baker’s yeast use a similar
mechanism.
The process begins by
unzipping DNA’s ladder-like structure, resulting in two strands called the
leading and lagging strands. A molecular construction crew then assembles the
missing halves of the strands, turning a single DNA helix into two. Much of this
work falls to enzymes called polymerases, which assemble the building blocks of
DNA.
On their own, however, polymerases
aren’t good at staying on the DNA strand. They require CTF18-RFC in humans and
Ctf18-RFC in yeast to thread a ring-shaped clamp onto the DNA leading strand,
and another clamp loader called RFC in both human and yeast to thread the clamp
onto the lagging strand. The clamp then closes and signals to the polymerases
that they can begin replicating DNA.
Using high-powered cryo-electron
microscopes, Li, O’Donnell and their teams revealed previously unknown facets
of the leading strand clamp loaders’ structures, including a “hook” that forces
the leading strand polymerase to let go of the new DNA strand so it can be
recognized by the clamp loader. This distinction represents a key difference
between the functions of the leading strand clamp loader (CTF18-RFC) and the
lagging strand clamp loader (RFC) and illuminates an important aspect of
varying DNA duplication mechanisms on the leading and lagging strands.
Lastly, the study identified shared
features between the yeast and human leading strand clamp loaders, which
demonstrate an evolutionary link between the two. This finding underscores the
value of yeast as powerful yet simple models for studying genetics.
Journal article: https://www.science.org/doi/10.1126/science.adk5901
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