Saturday, 10 October 2015

The 2015 Nobel Prizes

I just posted this on my Sheffield Undergraduate Blog site, but I covered some of this material in my lecture on Thursday at the UTC. So I thought I would post here too. There is a power-point link on the RHS in the "Interesting Links" box, click Nobels 2015. It may be a little hard going for those not taking A level chemistry, but see what you think! 

The recent Nobel Prize in Chemistry awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar (L to R opposite) provides a great example of just how powerful Biochemistry can be. It sits at the interface between Life Sciences and Chemistry, and can be instrumental in helping to elucidate the molecular basis of processes that are not only interesting in themselves, but also provide the foundations for future developments in medicine. 

The announcement made by the Nobel foundation last week, included the following phrase: “for mechanistic studies of DNA repair", which made me think immediately of the suggestion made to the Krebs Institute management board by one of our distinguished advisers, (Sir) Rich Roberts: "why don't you refresh the Krebs Institute mission..., how about mechanistic biology?". What a great concept, we all thought. The "strap line" was duly adopted, posted on the Institute web site,  incorporated into our grant applications and was bandied around at meetings just as much then, as it is now! Rich, a chemist by trade, obtained his PhD with David Ollis FRS, the head of Chemistry at Sheffield from 1963-1990. Rich always describes his project as simply being given a log from a Brazilian tree, and being told to find something interesting in it! Which he did pretty quickly! From every conversation I have had with Rich (and you can read the story he tells at these three blog posts: one, two and three), his understanding of Chemistry has always informed his Molecular Biology work: just take a look at Roberts RJ on PubMed

Getting back to DNA Repair, I can't think of many better examples of how the partnership of Chemistry and Biology, captured succinctly by the adjective "mechanistic",  has been so successful in explaining the underlying mechanisms of Darwinian evolution. In the absence of the advantages of the post Watson and Crick era, Darwin's ideas centred on a level of intrinsic  genetic change, on a "geological" timescale to explain the transitions in the fossil record. But mechanisms for change, or mutation, must be controlled in order that we don't stray too far from the "healthy" programme of reproduction and development. Without DNA repair mechanisms, we would succumb to diseases like cancer, much more frequently. Or as King Lear might have put it more eloquently:

Sans DNA repair... "O, that way madness lies"

What were the key pieces of work that led to the Nobel Committee's decision? As Tomas Lindahl commented when interviewed shortly after the announcement; there were perhaps a dozen scientists who contributed to our current understanding of the principles of DNA repair, so how did the committee pick out these three individuals? One way to find out is to take a look at their publication record: the time honoured way of assessing the "impact" of a scientist (you can read more about this here). Here are my own choices of a single paper from each of the three laureates. These papers exemplify the quality and strategies used by the laureates, and provide an insight into the quality of these worthy Prize winners.

In this paper Tomas Lindahl and colleagues at the Imperial Cancer Research Fund labs at Clare Hall (soon to be relocated with other London labs to the brand new Crick Institute), used a range of analytical techniques (protein purification, protease mapping and petide analysis by HPLC) to demonstrate that the adaptive response protein (ada) comprises two domains and that each domain can remove the alkylation damage conferred on guanines in DNA (a form of damage). In doing so, the alkyl group (eg a methyl) is transferred to a Cys residue in a conserved motif. The enzyme is subsequently inactivated and can no longer participate in repair functions (this is a suicide repair event, as far as the enzyme is concerned!). Interestingly, the ada protein has a second function: it can stimulate expression of the DNA sequence, encoding its own protein sequence! These incisive biochemical studies characterized the work from the Lindahl group over a period in excess of 30 years, of sustained, high impact science!  The image on the right was obtained by NMR later and both confirmed and added the molecular details to these landmark studies.

Escherichia coli mutS-encoded protein binds to mismatched DNA base pairs.  Su SS, Modrich P. Proc Natl Acad Sci U S A. 1986 83:5057-61.

PDB 1oh6 EBI.jpgPaul Modrich's lab at Duke University  (North Carolina) unearthed the mechanism of mismatch repair catalysed by a complex of enzymes that are referred to by their genetic names: MutH, MutL, MutS, and MutU from E.coli. I have picked a paper relating to MutS. This early publication demonstrates the similar approach taken by the Modrich lab (as Lindahl) in purifying and characterising functions using a combination of protein and nucleic acid chemistries. The lovely example in the paper of DNAse footprinting reveals evidence for mismatch recognition by the MutS protein. The structure shown left , once again confirmed the elegant biochemistry from Modrich's lab.

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Object name is zpq0450641240005.jpgFinally, the Turkish born Aziz Sancar, now at the University of North Carolina has brought a rigorous approach to understanding DNA repair (and latterly a related set of proteins associated with  Circadian Rhythm and cell growth in plants and animals). In the above paper, a little more recent than the previous two, Sancar's lab tackle the relationship in activity terms between the cryptochrome and photolyase encoded genes referred to as Cry-DASH. This paper illustrates the systematic approach to addressing a controversial issue relating to a set of genes/proteins that share evolutionary links. Once again, the conclusions drawn are supported by associated structural work: the structure of a Cry-DASH protein interacting with damaged single-stranded DNA is shown opposite.

In conclusion, the elegant experimental work of Lindahl, Modrich and Sancar shares a lot in common. Their identification and characterisation of the proteins that recognise and fix a range of lesions from mismatches, chemical modifications through to light induced pyrimidine dimers provided a starting point. These authors and subsequently numerous other groups have confirmed and extended the work and we are now beginning to harness these results for therapeutic applications. The interdisciplinary nature of this work: chemistry, biochemistry, molecular cell biology and medicine, fell into the Chemistry Prize category, but it seems to me that it could equally have earned the Prize in Medicine or Physiology. Congratulations to all three winners!

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