Mending the fabric of your genes

Mending your genes is a bit like mending your jeans, with many different scuffs, rips, and loose threads in need of repair. Scientists know that a specific kind of DNA threading mistake causes the repeated C-A-Gs of HD to get longer and longer. But could other kinds of genetic mending also be involved in HD? A research group decided to assess a broad range of DNA repair activities in HD mice, to see what other kinds of genetic repairs might be happening. They showed that mending of double-stranded DNA breaks is increased in brains of HD mice and might contribute to disease.

Too many C-A-Gs cause neurons to get sick

The repeating genetic letters C-A-G are responsible for causing HD when someone inherits too many in a row in a gene called huntingtin. Over the past few years, major advances in HD research have shown that these problematic threads of repeating C-A-G can get longer and longer in some vulnerable neurons, through a process called somatic expansion. By targeting somatic expansion, we might be able to preserve sick neurons and treat HD. However, scientists continue to debate how many repeated C-A-Gs cause a neuron to get sick and lead to HD and whether all expansions are harmful.

*Your body is constantly mending tears and rips in the DNA fabric of your cells, like a cherished pair of jeans. But sometimes this mending adds extra C-A-G thread by mistake. Image credit:* *Rodolfo Gaion*

Your threads of DNA are constantly being mended

Your genetic code is packaged up as a double-strand of DNA in every cell of your body, like an extraordinary thread woven into genetic fabric. But as with any fabric, it can fray and develop holes over time. Fortunately, your body has many ways to spot damage to DNA and is equipped with a range of tools to repair it. Sometimes this damage is a partial break of only one DNA strand, called a single-strand break, like a frayed spot in your jeans where some threads remain. Other times the DNA double strand breaks completely, called a double-strand break, like a complete tear that leaves a hole. The DNA double strand can also be paired incorrectly, called a mismatch, like a thread that snags and pulls out. Your body is constantly mending these different kinds of DNA damage to keep the vital genetic fabric of your cells intact.

A specific type of DNA mending adds more C-A-Gs

In recent years, HD researchers have dug deeper on a surprising insight about how HD develops: those growing C-A-G repeats that can accumulate and eventually become toxic seem to happen as a byproduct of your body’s attempts to mend mismatched DNA. You read that right – C-A-G expansions can happen when the body is trying to repair slipped threads of DNA. While the mending is normally beneficial, repairing a C-A-G thread can sometimes actually add a few extra C-A-Gs by accident, like a tailor adding too much thread. It is increasingly thought that this is how so many C-A-Gs accumulate and become toxic in neurons – through errors made in repairing mismatched C-A-G threads.

Could other mending mistakes be involved in HD?

Although scientists have found that DNA mismatch repair can cause extra C-A-Gs to accumulate, it’s not clear whether other kinds of DNA mending might also be involved in HD. Understanding which kinds of DNA mending are disrupted in HD is important for developing the right kinds of drugs to treat all aspects of the disease. That’s where a new study comes in: Drs. Aris Polyzos and Cynthia McMurray from the Berkeley National Laboratory decided to look at what other kinds of DNA repair might be involved in HD. They asked whether double-strand breaks of DNA – clean cuts in the genetic fabric – are also a feature of the disease.

*When a repeated C-A-G thread is mended, a few extra C-A-Gs are sometimes added by accident, like a tailor adding too much thread when fixing a hole.*

More loose threads – and more mending – in the HD brain

Think of all the different kinds of tears and scuffs that your favorite pair of jeans might encounter. Mending each specific tear might require different stitching or technique. In the same way, your body has a suite of tailoring tools for all the different ways that your DNA fabric can fray and become damaged. Polyzos and colleagues looked at the brains of mice with HD to see how much these different kinds of DNA mending are happening.

They found that the brains and neurons of HD mice have more mending associated with double stranded DNA breaks – a process distinct from mismatch repair. This raises an important question: does this mending of double-stranded DNA breaks happen in combination with accumulating C-A-Gs caused by mismatch repair, or does it happen independently? And might these double-stranded breaks be involved in HD?

Independent mending methods?

To try to answer this tricky question, the researchers looked at double-stranded DNA breaks in HD mice that have a lot of C-A-Gs but are engineered so that their cells are missing some of the machinery involved in mismatch repair. These mice engineered without mismatch repair don’t accumulate more C-A-Gs, since mismatch repair mistakes are how more C-A-Gs get added.

Interestingly, in both the HD mice that accumulate more C-A-Gs and the mice that don’t, there were still more double-stranded DNA breaks than in healthy mice.

These findings suggest that double-stranded breaks in the DNA fabric might be happening independently of mismatch repair and accumulating C-A-Gs.

The cells of your body are equipped with different techniques to mend the various kinds of rips and tears your DNA can encounter, much like a tailor with different kinds of threads and tools. Researchers have found that a specific kind of mending, called double strand break repair, is increased in brains of HD mice. Image credit: *Jahra Tasfia Reza*

What does this mean for HD?

In these experiments, the authors showed that different types of DNA damage – double strand breaks and mismatch repair – can happen independently of one another in HD mice. This means that preventing extra double-stranded breaks in DNA of the brain might also be important for treating HD.

There are still important questions about how these findings apply to people with HD. The researchers studied mice with far more CAG repeats than most people with HD inherit. At these very long repeat lengths, mice can develop disease-related changes even without further CAG expansion. This makes it difficult to establish whether DNA double-strand breaks contribute to HD in the same way in people, where CAG repeats typically start much shorter and can expand in some cells over many years. Further studies will be needed to determine whether these DNA breaks are a direct cause of neuronal damage in human HD, or one part of a more complex chain of events.

Nonetheless, this research continues to expand our understanding of what goes wrong in neurons of people with HD – and how to mend it.

Summary

The normal repair of your genes is what causes more C-A-Gs to accumulate, like a tailor fixing a hole using too much thread
A specific kind of mending called mismatch repair adds more C-A-Gs in the brain
New research shows that other kinds of mending are increased in brains of HD mice
Double-stranded DNA breaks accumulate in neurons of HD mice but it is still unclear how they contribute to HD in people

Mending the fabric of your genes

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Glossary

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