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Tomas Lindahl, pictured here in the lab, along with Paul Modrich and Aziz Sancar, received the Nobel Prize for Chemistry. EPA/FACUNDO ARRIZABALAGA

Nobel Prize in Chemistry highlights how our bodies can repair our fragile DNA

DNA is the fundamental building block of life. Every organism, from the simplest bacterium to plants, animals and humans contains a vast quantity of genetic information in the form of DNA.

DNA orchestrates the process of development through which single fertilised eggs grow into whole animals, which ultimately produce more fertilised eggs and yet more generations of animals.

DNA encodes the information that defines each species, and at the same time the subtle differences in this information make each individual unique. More cells are made as our bodies grow, and each cell needs its own complete, accurate copy of DNA.

When the structure of DNA was first discovered, initially it was thought to be chemically stable. More recently it became clear that DNA is damaged by all sorts of environmental chemicals like cigarette smoke, radiation such as X-rays and the UV radiation in sunlight.

In addition to environmental sources of DNA damage, during normal essential cellular processes our cells generate reactive chemicals that interact with and damage DNA. Moreover, the normal process by which our cells divide to either grow our bodies or maintain tissue is inherently prone to produce mistakes or DNA damage.

In fact it has been estimated that each cell in our body has to cope with more than 10,000 DNA damage events every day. Most of these are damage to the “base” or “nucleotide” building block components of DNA, or breaks to a single strand of DNA, and so repair of base and nucleotide damage and single strand breaks is critical for survival of all life.

While small changes in such large genetic codes may seem minor, some infrequent genetic changes can have drastic deleterious effects like blocking the proper development of the immune system and allowing development of cancer.

Dynamic fixers

The 2015 Nobel Prize in Chemistry has been awarded to the three fathers of the DNA damage field, Swedish scientist Tomas Lindahl, American scientist Paul Modrich and US-Turkish scientist Aziz Sancar, for their seminal work in the DNA repair field during the 1970s – 1980s.

Collectively, they defined that organisms are able to survive at all because they have very specialised processes involving cascades of enzymes which detect DNA damage and perform a triage-like step-by-step repair.

Royal Swedish Academy of Science

Lindahl challenged the dogma that DNA was a stable molecule during the 1970s, where he demonstrated that organisms should be not able to survive given the constant onslaught of DNA damage they are exposed to.

He discovered the base excision repair pathway, a mechanism that fixes missing bases or inappropriate chemical modification of bases. Modrich discovered a different form of DNA repair which corrects mismatches, or copy errors which occur when our DNA is replicated before cells divide.

Royal Swedish Academy of Science

Sancar characterised the nucleotide excision repair pathway, which addresses bulky DNA adducts and damage caused by UV radiation, which can kink the DNA strand. The initial discovery and characterisation of these pathways has led a burgeoning field of research into how cells detect and repair damaged DNA.

Royal Swedish Academy of Science

DNA paradox

As well as providing the fundamentals for understanding how cells function normally, and the defects that underlie human diseases like some types of immune-system failure, neurological degeneration, cancer, and ageing, our understanding of DNA repair has offered remarkable opportunities to improve health.

For example, almost all cancers exhibit a phenomenon known as “genome instability” – accumulation of DNA damage which is inadequately repaired. This may occur through inherited changes in genes required for DNA repair (e.g. mutations in the BRCA1 and BRCA2 genes predisposing to breast and ovarian cancer and in mismatch repair genes predisposing to hereditary form of colon cancer) or through prolonged exposure to DNA damaging sources (e.g. UV radiation and skin cancer). Paradoxically, it is this very feature which renders cancer cells more susceptible to killing by additional sources of DNA damage, such as radiation therapy and some forms of chemotherapy.

As researchers begin to decode the intricacies of how DNA damage is detected and repaired, it is leading to a rapidly developing field of targeted cancer therapy –where DNA repair defects in individual cancers can be exploited for more effective and less toxic treatment.

Harnessing our new understanding of DNA repair has also facilitated the development of technologies that will fundamentally change the way we approach diverse challenges, like biological research, agriculture and treatment of genetic disorders.

The recent invention of DNA-repair dependent gene-editing (CRISPR/CAS9) has the potential to cure DNA mutations that underlie genetic diseases. A specific example of this might be to use DNA repair to “fix” the damaged copies of the CFTR gene which cause cystic fibrosis.

Lindahl, Modrich and Sancar have been at the forefront of DNA damage research since they challenged the dogma of the time and carved out a whole new field of research in the 1970s.

Their fundamental biochemical discoveries have had wide-ranging positive impacts on our approach to biology and medicine. As DNA repair researchers it is exciting and inspirational for us to see pioneers of the field awarded the 2015 Nobel Prize for Chemistry.

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