The Nobel prize – the most prestigious accolade that can be awarded to a human dead or alive. This year the Nobel prizes for science were awarded in physics for the discovery of neutrinos having mass, in biology for the treatment of roundworm parasite infections and the real stand out discovery of DNA repair mechanisms in chemistry.
DNA replication occurs constantly in every dividing cell in our body and involves the unzipping of the double helix by an enzyme called DNA helicase; DNA polymerase (another enzyme) then incorporates new bases to complimentarily match the template DNA strand. As this happens constantly in our cells, DNA polymerase is bound to make mistakes occasionally, inserting the incorrect bases, consequently damaging the DNA. Some of these mistakes are required for natural selection and evolution, however, some non-silent mutations can cause devastating effects. Nevertheless, we have adapted a multitude of repair mechanisms to avoid potentially fatal DNA damage, these mechanisms are the topic of this years chemistry Nobel prize.
DNA damage not only occurs from replication but can also be due to exposure to chemicals or radiation of which the most likely to encounter is UV. Aziz Sancar has discovered the mechanism of ‘nucleotide excision repair’ (NER) that repairs UV damage to DNA along with damage caused by mutagenic substances. People who lack this repair mechanism as a genetic default (eg. sufferers of Xeroderma pigmentosum) are very sensitive to UV and easily develop skin cancer if exposed to sunlight as their UV damaged DNA cannot be repaired. Sancar has discovered 3 main proteins involved in NER UV
repair, uvrA, uvrB and uvrC. The mechanism of their action initiates with uvrA and uvrB forming a complex called uvrA2B; the A subunits recognise the damaged section of DNA and the whole complex stops at the site where partial unwinding then takes place by DNA helicase (activated by the B subunits). This unwinding causes the DNA to kink and enables the uvrB subunits to also recognise clearly that this is damaged DNA. With uvrB bound to the damaged DNA, the A and B subunits dissociate from one another and uvrC binds to the uvrB-DNA complex. This activates uvrB causing it to hydrolyse a phosphodiester bond (the 4th or 5th bond in the 3′ direction from the damaged area) simultaneously with uvrC hydrolysing a second phosphodiester bond (8th bond in the 5′ direction from the damage) thus creating a fragment of ca. 12-13 bases long. Finally, DNA helicase II (also called uvrD) displaces the damaged DNA strand, RNA polymerase I associates with the remaining DNA and fills the excised gap with new correct bases, before DNA ligase seals up the ends by forming two new phosphodiester bonds.
Lindahl shares the Nobel prize this year due to his discovery of the base excision repair (BER) mechanism. Our cells contain a variety of DNA glycosylases identifying mutated bases via interactions with the base in their specific recognition pocket, upon recognition they hydrolyse the glycosyl bond between the faulty base and the deoxyribose sugar. This causes a kink in the DNA which kicks the mutated nucleotide out of the DNA base sequence. An apurinic or apyrimidinic endonuclease displaces the DNA glycosylase before associating with DNA polymerase to fill in the base that has been excised. The final step is for DNA ligase to displace the DNA polymerase and catalyse the formation of a new phosphodiester bond.
A final repair mechanism revealed is the mismatch repair mechanism. If a base is wrongly incorporated, non-Watson and Crick base pairs are formed which distorts the double helix structure as the number of hydrogen bonds between the base pairs is wrong and as each base is a different size, the wrong base doesn’t fit into the site correctly, changing the distance between the adjacent bases. These mismatches can permanently alter the sequence of DNA causing mutations if not quickly corrected. The mismatch repair mechanism is one of proof reading that minimises error and mutations by approximately a thousand fold, and utilises a 3′ – 5′ exonuclease activity of the DNA polymerase which checks the newly synthesised 5’ to 3’ strand. If an error is found, the direction of the polymerase (5’-3’) is reversed and it excises incorrect bases, although some mismatched bases will always remain as this is not 100% efficient. The complete mismatch repair mechanism is not fully understood yet but Paul Modrich’s work so far in this area of work has accredited him with the remaining third of the Nobel prize this year.
As cancer cells divide more rapidly than healthy cells and can accumulate an impressive range of mutations in doing so, these discoveries on how cells repair damaged DNA may be invaluable in coming years for the specific targeting of cancer cells. Is this one step further to finding the cure for cancer? Only time will tell.