When DNA Repair Goes Off Script: How a Small Change in FAN1 Can Accelerate Huntington’s Disease

Two research teams have uncovered how a small change in FAN1, a DNA repair protein, can speed up Huntington’s disease (HD). In back-to-back papers in Nature Communications, they show how a single mutation known to influence when symptoms begin appears to prevent FAN1 from working properly. This seems to make it harder for cells to keep harmful DNA changes in check. Let’s look at what they found.

DNA Repair and Repeat Expansions in HD

Keeping our genetic material in check is a constant job for the cells of our body. Our DNA is under constant stress from all kinds of damage, ranging from UV damage caused by the sun to correcting molecular errors to ensure new mutations aren’t made, and cells rely on a network of repair proteins to fix problems before they cause harm.

The role of these DNA repair players has been shown to be important in HD. In particular, many different teams of researchers have shown that the C-A-G DNA letter repeat region of the HTT gene can get longer and longer over time in some types of cells. This so-called somatic instability, or somatic expansion, is thought to play a central role in how early and how severely the disease appears.

FAN1 is one of several proteins that help manage these repetitive DNA sequences, typically preventing them from expanding over time. Another key player in this repair process is PCNA, a protein that acts like a supporting actor, helping the leading players, including proteins like FAN1, stay on script during DNA repair.

The R507H Mutation in FAN1

Generally, the longer the CAG number someone has, the earlier they will begin to experience symptoms of HD. However, we also know that for two people with the exact same CAG number, their symptoms may begin decades apart. This is in part due to things called genetic modifiers: other DNA changes in the genome, aside from the HD mutation, which are associated with differences in when symptoms begin.

Some people with HD carry a specific change in the FAN1 protein, known as the R507H mutation. While this might seem like a confusing code, the letters and numbers let researchers know precisely where and what the change is, like the page and line numbers in a script – at the 507th spot within FAN1, an “R” protein building block is swapped for an “H”.

This single-letter change alters just one building block in a protein of more than 1,000 building block letters, or amino acids. Although it’s a small change, people carrying this FAN1 variant tend to develop symptoms much earlier than expected based solely on their CAG number. Until now, the reason behind this link wasn’t well understood.

Using powerful microscopes, researchers were able to visualize how FAN1 normally binds to PCNA. This binding allows FAN1 to position itself properly onto DNA to carry out its repair work. But the R507H mutation weakens this interaction, reducing FAN1’s ability to hold on to PCNA and stay in place during repair.

A Closer Look at the Consequences

Both studies examined the effects of the R507H mutation in detail. One found that FAN1’s ability to cut the loops that form in CAG repeats in DNA seemed to be reduced. The other suggested that the entire FAN1–PCNA–DNA complex was less stable and less effective at DNA repair when the R507H mutation was present.

These DNA loops are also called extrusions, as they stick out awkwardly from the DNA helix, like a stage prop out of place. These extrusions tend to form in regions with many repeats, like the CAG tract in the huntingtin gene. The longer they are, the more unwieldy they become. If not properly repaired, they can lead to further expansions, making HD symptoms worse over time.

Why This Matters

These findings offer an explanation as to why the R507H mutation might be linked to earlier HD onset: the mutation disrupts FAN1’s repair activity, which can lead to faster accumulation of harmful DNA changes, and more somatic expansion. Overall, this could explain why this genetic modifier hastens the onset of HD symptoms.

These detailed insights into how FAN1 can go off script in some people with HD not only deepen our understanding of the disease, but also open up new directions for treatment. By mapping out the exact role of FAN1 in HD pathology, researchers can begin to explore ways to restore proper repair function, for example, by designing therapeutics that stabilize the FAN1–PCNA interaction or by boosting FAN1 levels.

And there are companies already doing exactly that! For example, Harness Therapeutics is working on developing specialized DNA molecules, known as antisense oligonucleotides or ASOs, that are designed to boost production of FAN1, with the overall aim of making the C-A-G repeat shorter.

While much of HD therapeutic research has focused on lowering levels of the harmful huntingtin protein, these results suggest that strengthening the cell’s natural DNA repair processes could offer another way to slow disease progression. Perhaps this could one day be applied together with huntingtin lowering. The more approaches we explore, the greater the chances of finding an effective therapy for HD.

Finally, recognizing this mutation in people with HD may help tailor care strategies in the future, pointing toward a time when therapies are prescribed based on each person’s genetic makeup.

Moving Forward

Thanks to these two new studies, we now have a clearer picture of how a small change in FAN1 can tip the balance, accelerating the progression of HD. This insight was only possible because of the generosity of HD families around the world who contributed samples to the large genetic studies that first identified this variant.

With more research, we may one day be able to correct or compensate for that shift, helping people with HD live healthier, longer lives.

Summary

• FAN1 is one of several DNA repair proteins that help keep repetitive DNA sequences in check.
• A specific change in FAN1, called R507H, seems to reduce its ability to interact with PCNA, another key repair protein.
• This disruption appears to make it harder for cells to manage CAG repeats in the huntingtin gene, potentially accelerating HD onset.
• Understanding this process opens the door to new therapeutic strategies, such as stabilizing DNA repair pathways.
• These insights were made possible thanks to HD families worldwide, whose contributions to genetic studies enabled the discovery of this mutation.

Learn more:

“A FAN1 point mutation associated with accelerated Huntington’s disease progression alters its PCNA-mediated assembly on DNA” (open access).

“Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair” (open access).