Science

Key Studies on How DNA Gets Damaged and Repaired Win Chemistry Nobel

(L to R) Aziz Sancar, Paul Modrich and Tomas Lindahl, winners of the Nobel Prize for chemistry in 2015, for their study of DNA repairs. Source: nobelprize.org

(L to R) Aziz Sancar, Paul Modrich and Tomas Lindahl, winners of the Nobel Prize for chemistry in 2015, for their study of DNA repairs. Source: nobelprize.org

The Nobel Prizes for chemistry have actually been awarded more often through history as the Nobel Prizes for biochemistry – having often gone for discoveries of chemical reactions inside living beings. And the trend continues this year too, with Tomas Lindahl, Paul Modrich and Aziz Sancar winning the 2015 prize for their “mechanistic studies of DNA repair”.

The DNA molecule preserves humans’ genetic information and describes how similar we are to our parents, besides dictating many things about how our bodies are supposed to function. The molecule contains information as a series of pairs of bases arranged like the rungs of a ladder twisting clockwise. The rungs are cytosine (C) bonded with guanine (G) and adenine (A) with thymine (T). Sometimes, damage to this ladder – by cancer, smoking, the rare mutation, etc. – can cause the DNA to issue wrong or faulty instructions to our bodies and cause various ailments. Fortunately, our body has developed many chemical systems to fix these damages.

Swedish biologist Tomas Lindahl announced in 1974 the first discovery of one such system. The DNA molecule has limited chemical stability and is sometimes damaged by chemical reactions happening within the cell that houses it. At such times, the C-G bond (i.e. rung) breaks as the C turns into a U (uracil). Lindahl found that the U is turned back into a C by the excision repair system.

Lindahl’s work was conducted in the 1960s – soon after the double-helical structure of DNA was identified by Rosalind Franklin, James Watson and Francis Crick in 1953. In some ways, his receiving a third of the chemistry prize over 50 years later is a lifetime-achievement award. Lindahl is 77.

Paul Modrich, an American, was lauded for his discovery of the DNA-mismatch repair system. When a cell in our body divides into two, it makes a copy of its DNA for the new cell. But on rare occasions, the sequence of base-pairs is not replicated exactly, resulting in a mismatch. Modrich and compatriot Matthew Meselson found over the 1970s that some proteins in our body could recognise the mismatch as well as the strand that had been wrongly synthesised. In fact, it was Meselson’s idea – as the Nobel Foundation notes – that the strange protein behaviour he and Modrich were observing could be part of a repair mechanism. They went on to find that the proteins could and did resysnthesise the new DNA strand.

Animation showing the DNA double-helix structure. Credit: Wikimedia Commons

Animation showing the DNA double-helix structure. Credit: Wikimedia Commons

A third kind of damage was found to happen when the DNA molecule was exposed to UV light or chemicals entering the body because of cigarette smoking. In such cases, adjacent Ts (thymines) on one side of the DNA ladder could form a chemical T-T link between themselves and disrupt the DNA’s normal functioning. Aziz Sancar, a Kurdish scientist who has worked in both his native Turkey as well as the United States, discovered the nucleotide excision repairs. In this case, certain proteins would cleave the DNA on either side of the T-T link and cut away the damaged part of the strand. Then, they would synthesise a new, chemically correct piece of DNA and fuse it in. Voila!

All together, the three scientists’ work helps explain the basic molecular reactions “that guard the integrity of our genomes”, as the presentation following the prize’s announcement concluded, as well as teaching us of how chemistry was protecting us. For example, the mismatch repair system found by Modrich and Meselson reassured us that our bodies had hiked the fidelity of DNA replication by a factor of 1,000. Yet, despite these great insights into life at almost its finest levels, there remain many chemists who will now have been passed over for work done in studying DNA repair systems.

Meselson himself is an example as well as a casualty of the Nobel Foundation’s now-outmoded adherence to the rule that no more than three people can be awarded the prize at once. The Foundation has also ignored this year’s winners of the Lasker Award – considered the second-most prestigious among physiologists after the Nobel Prize for medicine: Stephen Elledge and Evelyn Witkin. Their award’s citation reads, “For discoveries concerning the DNA-damage response – a fundamental mechanism that protects the genomes of all living organisms”. Adding to the embarrassment is that in its selection, the Nobel Foundation has also glossed over contributions by female scientists.

Similarly, Sancar’s work coincides with the years – again, the 1970s – in which the Croatian-French scientist Miroslav Radman had made advancements in understanding how DNA responded to damages due to UV irradiation. The list goes on.

Evidently, modern studies of the DNA molecule have roots in many researchers working separately around the world but over the same decades, with the subject’s complexity encouraging diverse approaches and efforts. The story of the discovery of the molecule’s structure itself has so many characters and much drama – such has been the appeal of this deceptively elegant chemical compound. In 2015, Lindahl, Modrich and Sancar may deserve their award, but three faces are far too few to represent our insights into our genome.