Surprising twists and turns come to light in the way cells are copied
“Expect the unexpected” might be the motto for Anja-Katrin Bielinsky’s laboratory.
“Everything was a surprise,” she says of her discoveries so far. “The theme of my independent career has been stumbling into unknown problems.”
An associate professor of biochemistry, molecular biology and biophysics, Bielinsky explores the mechanisms behind the process by which a cell replicates its genetic material before it divides.
The star of the show is a molecular machine that inserts itself between the two complementary strands of DNA and uses them as templates for two new strands. In bacteria, scientists have a pretty good idea of how the resulting configuration, known as a replication fork, works. But in eukaryotic organisms—that would include you and me—the process is much less clear.
Bielinksy, whose work is supported in part by the Leukemia and Lymphoma Society, has been looking at replication in yeast and human cells to understand how replication forks form, what they do and what happens when they don’t do what they’re supposed to.
A particular focus of her attention is DNA polymerase α, a protein required to start replication. It reads the templates and assembles the new DNA strands. Looking for clues as to how it does its job, Bielinsky was surprised to discover that it owes its success to another molecule. MCM10 chaperones polymerase α to the replication site, then stands by to keep it stable while it does its job.
“If you take that out, the whole structure falls apart,” she says. “Nobody expected that.”
In another surprising turn, Bielinsky and colleagues discovered that the replication fork is responsible not only for copying DNA, but also for recognizing whether the DNA it is about to copy is damaged and, if so, putting the process on hold until it can be repaired. The fork even looks back at DNA it has already copied to see if there are problems there, and at the new strands to make sure they’re okay too.
“This came as a complete surprise,” she says. “For many years, people thought the fork would just move on, regardless of what happens behind it. It turns out the cell is so much smarter than we thought.”
Recently, Bielinsky teamed up with Brandt Eichman of Vanderbilt University to solve the crystal structure of MCM10. That means they can now explore how the shape of the molecule relates to its interactions with other proteins and DNA.
Bielinksy is currently looking at other parts MCM10 might play at the replication fork, as well as working to understand how it connects with DNA polymerase α, how it keeps DNA polymerase α from falling apart, and what controls the chaperone molecule’s comings and goings.
“It’s really very thrilling,” Bielinksy says. “Every week there’s something I didn’t expect. It’s very unsettling—in a good way.”
Understanding how the replication fork works can provide clues to preventing cancers that result from DNA fractures that occur when replication goes awry. And, because MCM10 is such a linchpin in the replication process, this helper molecule could make a good target for new therapies to halt the uncontrolled cell division that is a hallmark of cancer. —Mary Hoff
