Happy DNA Day! Join us in celebrating the foundation of life as we know it by learning about innovative DNA-focused research in our department.
Before we dig into the research, let’s pause for a moment to really appreciate how cool DNA is and how important it is for our survival as individuals and as a species.
DNA, or deoxyribonucleic acid, is the highly protected biological cookbook that resides in each and every one of our cells. It has two main jobs – to store and share recipes needed to maintain life in every cell in our body, and to pass accurate information on to the next generation of cells / chefs. To do these two jobs well, it is critically important that the sequence of the DNA remains unchanged. Unfortunately, the sequence of our DNA, like the text in a well-used cookbook, faces a lot of challenges to its integrity throughout our lives. Similar to how a word in a cookbook might get splashed with water in the kitchen and smudge the words beyond recognition, the “sentences” or genes in our DNA can be damaged to the point where the original sequence of the gene is changed. These changes in the DNA sequence are also known as mutations. DNA mutation can have serious consequences, including diseases in an individual like cancer or diseases in offspring like cystic fibrosis.
Luckily, DNA has a strong defense against damage – it protects itself by being “double stranded.”
This would be like two pages in a cookbook that are able to stay stuck together and protect the information inside by fitting together like puzzle pieces. DNA has two complementary strands that are linked together to protect the information within. There is one flaw in this defense system, though – for DNA to be copied when a cell divides, the two strands have to be pulled apart so the cell can correctly read the information inside. This opens up the single strands of DNA to lots of opportunities for mutation.
Illustration of the Deoxyribonucleic Acid (DNA). Left: DNA comprises nucleotide base pairs: Adenine, Thymine, Guanine, and Cytosine, linked horizontally by hydrogen bonds. The backbone of the DNA strand is made from alternating phosphate and sugar groups. Right: Double-stranded DNA is protected, while single-stranded DNA is open and vulnerable.
So how do our cells handle this delicate balance between the necessity of DNA replication and the inherent dangers in splitting apart the two strands of DNA?
Well, organisms across the tree of life use a whole cadre of tools to protect their DNA while it is being replicated in the cell. One of the core proteins involved in DNA replication is shaped like a ring, and it acts as a clamp to hold a single strand of DNA while it is being copied and helps coordinate the entire replication process.
But you may have noticed a problem here: how does a closed ring/clamp get onto a strand of DNA in the first place?
Our DNA is so long, if we unwound the DNA from a single cell in your body, it would stretch to be just a little bit taller than world famous wrestler and actor, Dwayne “The Rock” Johnson; so it doesn’t make sense to slide the ring/clamp from the end of the DNA strand to where it needs to be. Enter, the DNA clamp loader. Clamp loaders are the part of the DNA replication machinery that is most similar across all life as we know it, and they do the important job of opening up the DNA replication rings/clamps, putting them onto a single strand of DNA, and closing them again.
Illustration of the bacterial clamp loader in complex with the bacterial sliding clamp holding a fragment of double-stranded DNA. Left: Protein structure from the PDB coordinates 8VAQ. Right: A rotated view of each bacterial clamp loader and the bacterial sliding clamp with each of their subunits.
The Kelch Lab in our department recently made some fascinating discoveries about how clamp loaders work. Specifically, they discovered that, even though eukaryotic (e.g. humans) and bacterial clamp loaders look very similar, they actually work in slightly different ways. One of their biggest discoveries was that bacterial clamp loaders grab onto replication rings/clamps and open them by pivoting at one point, like opening a door; while eukaryotic clamp loaders open replication rings/clamps by pivoting at multiple points, like those old-timey screens people used to use to divide up larger rooms.
The Kelch Lab discovered the differences between the bacterial and the eukaryotic clamp loader-sliding clamp complexes. Bottom illustration from Landeck et al., 2024. JBC.
This difference in the physical movement of the clamp loaders opens up new possibilities for antibiotic development.
If we can figure out a strategy to target the way bacterial clamp loaders move that wouldn’t affect how eukaryotic (human) clamp loaders do their job, then we could create new antibiotics that would slow down bacterial growth without affecting our own cells. This could potentially save lives around the world as antibiotic and antimicrobial resistance continues to rise (learn more about that in another blog post here).
Check out the Kelch Lab website to learn more about their groundbreaking research, or check out their most recent publication highlighted in this blog. As structural biologists (researchers interested in the physical shapes and movements of molecules inside our cells), they are constantly exploring the frontiers of our knowledge about how our cells work. We are lucky to work alongside them in our department to discover new ways to make our lives better.
