How often does your DNA get damaged?

The picture almost everyone has is wrong

DNA is usually described as a blueprint, an archive, the permanent record passed from parent to child. That framing suggests something stable, filed away and left alone. It is the opposite of what the molecule is actually like.

DNA is a long, fragile chemical sitting in warm salty water inside every one of your cells. Water alone slowly knocks letters out of it. Oxygen, the same oxygen your cells burn for energy, attacks it as a side effect. And that is before anything from the outside world arrives.

In the early 1970s this was not the mainstream view. Tomas Lindahl decided to measure how fast DNA falls apart on its own, and found rates so high that, as the Nobel committee later put it, DNA decays at a rate that ought to have made the development of life on Earth impossible. The numbers ruled out the archive picture entirely.

Where the damage comes from, and how much of it there is

Some damage is spontaneous. Letters fall out of the strand, and others quietly change chemical identity, so the text says something different from what it said yesterday. Reactive by-products of ordinary metabolism nick the backbone. None of this requires you to do anything at all.

Some damage comes from outside. Ultraviolet light carries enough energy to fuse two neighbouring T letters into a single kinked unit, called a thymine dimer, which the cell can no longer read. That is what a sunburn is at the molecular level, and it starts long before skin turns red. Carcinogens in cigarette smoke bind to DNA and leave bulky lesions of their own, a lesion being the damaged spot itself.

Then there are copying errors. Every time a cell divides it has to copy all six billion letters of its DNA. The copying machinery works at speed, and speed costs accuracy. Tens of billions of cells divide in your body every day, each division an opportunity for typos.

Adding it all together, a widely cited review in the New England Journal of Medicine estimates on the order of 10,000 to 100,000 lesions per cell per day, including thousands of single-strand breaks and thousands of spontaneously lost bases. Multiply by the number of cells you have and the daily total across your body is astronomical.

Why you are still here: the repair crews

The reason the damage does not simply accumulate is that your cells run continuous repair. The 2015 Nobel Prize in Chemistry went to Tomas Lindahl, Paul Modrich and Aziz Sancar for mapping three of these systems, each specialised for a different kind of damage.

Base excision repair, which Lindahl worked out, deals with letters that have decayed on their own: it removes the damaged base and rebuilds the spot. Nucleotide excision repair, mapped by Sancar, handles the bulky lesions from ultraviolet light and chemicals: an enzyme finds the damage, cuts the strand, lifts out a patch of about twelve letters, and the gap is refilled. Mismatch repair, mapped by Modrich, proofreads freshly copied DNA and corrects typos, cutting the replication error rate by roughly a thousandfold.

All three rely on the same trick. DNA is double-stranded, and each strand is the mirror image of the other. When damage lands on one side, the intact strand opposite is a full instruction for what the damaged patch should say. The spare copy is built into the structure of the molecule.

What happens when a crew is missing is not theoretical. In xeroderma pigmentosum, a rare inherited condition, nucleotide excision repair does not work. The sunlight damage still arrives, and nothing clears it. According to GeneReviews, the risk of non-melanoma skin cancer runs more than 10,000 times higher than in the general population, with a median age of onset of nine years, roughly 60 years earlier than usual. Internal cancers are about 34 times more common and arrive around 50 years early, because the same crew clears chemical damage that has nothing to do with the sun.

The same logic runs in the other direction in medicine. Some tumours have already lost a repair pathway, which makes them dependent on a backup, and drugs that block the backup kill them while healthy cells, which still have both, survive. The first of these was olaparib, approved by the FDA on 19 December 2014 for ovarian cancer in women carrying a faulty BRCA gene.

So the honest answer is tens of thousands of times a day, in every cell you have. A genome stays readable because the crews clear the day's damage before the next day's arrives, and they have been doing it every day you have been alive.