Michael Sean Pepper, University of Pretoria

Imagine a world in which nothing could go wrong. Completely predictable, without risk and with guaranteed equality for all. This utopia of course does not exist. It’s therefore not surprising that even Mother Nature can’t maintain complete fidelity in the most intimate element that defines who we are: our DNA.

To compensate for this imperfection, she has developed a system of DNA repair constantly at work in our bodies to make sure our DNA’s integrity is maintained.

For their work on the discovery of DNA repair mechanisms, three scientists – Tomas Lindahl, Paul Modrich and Aziz Sancar – have this year been awarded the Nobel Prize in Chemistry.

Their discovery is one of biology’s most important safeguards against imperfection in DNA, arguably the most important molecule we know. This intrinsic repair mechanism is however itself susceptible to imperfection. And when our DNA cannot repair itself, it may result in us developing diseases.

The story of DNA

We originate from a single cell, the fertilised egg. Through an extraordinarily well co-ordinated series of events this cell divides to become two, then four, then eight cells and so on until a complete organism is formed. The adult human is made up of 100 trillion cells. This means that cell division needs to occur up to a trillion times during the development of a human from a single fertilised egg.

The genome of every individual is unique. We inherit three billion (3 000 000 000) base pairs of DNA from each of our parents. This means there are six billion base pairs in the nucleus of every (nucleated) cell in the body. If stored in book form this can be equated to 6 000 books each containing 1 000 pages with 1 000 letters on each page. And all of this is to be found in a structure which is invisible to the naked eye!

About 1.5% of our DNA makes up the 20 000 genes which code for proteins which determine the structure and function of our bodies. Much of the remaining non-protein coding DNA has a critical regulatory function. Our notion of “junk DNA”, or DNA which serves no purpose, has almost completely disappeared.

We inherit mutations from our parents' DNA in their sperm and egg when we are conceived. The DNA in our own cells acquires additional mutations in the course of our lives. Most of these mutations are caused by everyday exposure to things like UV light and chemical toxins. Other mutations happen when the vast quantity of DNA contained in each nucleus replicates during cell division.

Changes in DNA can cause disease when critical cell functions are compromised. When the disease arises from changes in a single gene, geneticists use the term monogenic. Although these diseases are relatively rare, collectively they affect one in 200 people and there are more than 10 000 diseases known to be monogenic in nature. These include cystic fibrosis, muscular dystrophy and sickle cell anaemia.

More common diseases such as heart disease, diabetes and autoimmunity are considered to be polygenic or multifactorial. This means many genes are implicated in their cause and that there is an important environmental component at play.

When DNA can’t fix itself

This is where the DNA repair mechanisms discovered by Lindahl, Modrich and Sancar become important. Every day there are tens to hundreds of thousands of lesions in our DNA. Most are fixed by the repair mechanisms. These mechanisms are critical to maintain normal DNA which in turn is required to maintain normal bodily structure and function.

But like all other cell processes, DNA repair mechanisms can be compromised. Since the DNA repair mechanism has its origins in the DNA it repairs, defects in its function can also be inherited in a manner that is similar to other genetic disorders.

People who inherit defects in DNA repair are prone to certain types of cancer and to various diseases of the nervous system. One of the best known disorders of DNA repair is a rare disease called xeroderma pigmentosum. People who have this disorder have extreme sensitivity to UV light and a high likelihood of developing skin cancer in childhood. One third of affected people also develop disorders of the nervous system.

Understanding the fine molecular details of DNA repair mechanisms, for example, will assist in the development of new treatments for diseases which arise from defects in the process, including cancers.

It has been more than ten years since the sequence of the human genome was first reported. Although direct benefits to health have been slow to emerge, the genomic revolution is upon us and will impact heavily on our everyday lives in the years to come.

The Conversation

Michael Sean Pepper, Director of the Institute for Cellular and Molecular Medicine, University of Pretoria

This article was originally published on The Conversation. Read the original article.