SEP 21, 2020 7:47 AM PDT

Replicating the Genome With a Twist

WRITTEN BY: Carmen Leitch

The genome has to be perfectly copied every time a cell divides, and cells divide constantly, first to grow a developing organism, and then to maintain it; replenishing those cells that are old or dysfunctional. The replication of the genome starts with a set of proteins known as the Origin Recognition Complex (ORC). Dysfunction in the human ORC has been linked to developmental disorders and some types of cancer, so it's important to understand how it functions. Detailed images of the ORC and its dynamic movement around DNA have now been created and reported in eLife.

It's thought that the complex's first piece, ORC1, finds the genomic location where replication is supposed to start, and there, the other subunits of the ORC, 2 through 5, assemble. In the yeast genome, there is one sequence of DNA sprinkled through the genome that spells start, while in humans, it's more complex, and the start site or sites have not been found, yet.

"When the cell has to duplicate, the first thing that has to happen is that the genome has to duplicate. And so the positioning of ORC on these so-called 'start sites' is really the first event that has to happen in order to start the duplication of the genome," said Cold Spring Harbor Laboratory (CSHL) Professor & HHMI Investigator Leemor Joshua-Tor.

"You know, in bacteria, there's usually one start site because it's a small genome, but in larger organisms like humans, in order to be able to replicate such a large genome, what the cell does is uses many, many start sites. And the interesting thing in mammalian systems is that we actually don't understand what a start site really looks like."

A human Origin of Replication Complex (ORC); the complex clamps down on DNA (the red helix in the central model). On the left, the model shows the complex covered and protecting the DNA binding cavity, and on the right the complex has no DNA and is open. / Credit: Joshua-Tor lab/CSHL, 2020

The researchers identified ORCs in different organisms and found that they don't have the same shape. They determined that the shapes vary because the ORC has to twist and pinch in significant ways, which depend on what they have to do at any given time. In yeast, the ORC tends to freeze into one stable shape, while it takes on a different stable shape in flies.

 CSHL staff scientist Kin On said "the yeast complex is so stable, it is rock solid. But the human ORC assembly is very dynamic."

The team used careful sample preparations, cryo-electron microscopy (cryo-EM), and computational tools to capture the human enzyme complex taking on different shapes. One resembles a fly ORC while at another time it looks like an ORC from yeast. They've also taken the first snapshot of a human ORC as it surrounds a DNA molecule, a critical part of understanding them.

While this may help us learn more about disease and medicine, a greater understanding of basic biology is also still a worthy pursuit.

"How we duplicate our genome is the most basic process of life, right? Really that's what life is all about. So, regardless of how we understand cancer and this developmental syndrome, you know, understanding ourselves and understanding the most basic process, that is part of the human endeavor really to understand ourselves," said Joshua-Tor. "So it's not all about the utility of it...one of the basic endeavors...of humanity is trying to understand life and ourselves. I think it's a big part of why we're doing it. At least a big part of why I'm doing it."

Sources: AAAS/Eurekalert! via Cold Spring Harbor Laboratory, eLife

About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
AUG 10, 2020
Genetics & Genomics
A Mysterious Ancestor of Humans May Lurk in Some Modern Genomes
AUG 10, 2020
A Mysterious Ancestor of Humans May Lurk in Some Modern Genomes
Modern humans are exclusively Homo sapiens, but at one point, other related species were also present in the world. Nean ...
AUG 26, 2020
Cell & Molecular Biology
Levels of RNA Transcripts From 'Junk' DNA Get Higher as We Age
AUG 26, 2020
Levels of RNA Transcripts From 'Junk' DNA Get Higher as We Age
There is a lot more to the genome than just genes that code for proteins.
AUG 27, 2020
Cardiology
Are Dry Mouth and Hypertension Connected?
AUG 27, 2020
Are Dry Mouth and Hypertension Connected?
Dry mouth is one of those things you sort of ignore until you can refill your water bottle. Maybe you should take a seco ...
AUG 30, 2020
Genetics & Genomics
Brown Fat Transplants Could Reduce Metabolic Disease
AUG 30, 2020
Brown Fat Transplants Could Reduce Metabolic Disease
The Centers for Disease Control and Prevention (CDC) estimates that in 2018, obesity impacted about 42% of American adul ...
OCT 20, 2020
Genetics & Genomics
The Gene Behind the Glow of the Sea Pickle is ID'ed
OCT 20, 2020
The Gene Behind the Glow of the Sea Pickle is ID'ed
In this photo by OceanX, researchers off the coast of Brazil collected Pyrosoma atlanticum specimens with a special robo ...
OCT 24, 2020
Genetics & Genomics
Cord Blood Samples Reveal More About the Genetics of Autism
OCT 24, 2020
Cord Blood Samples Reveal More About the Genetics of Autism
The activity of genes in our genome is controlled by many factors, one of which are chemical tags or structural changes ...
Loading Comments...