Noble Prize Winners In Chemistry 2015

MECHANISTIC STUDIES IN DNA REPAIR

Every day the DNA held within our cells is constantly subjected to assaults from the environment, such as UV radiation from the Sun. But it’s not just external factors that we need to worry about. Despite scientists originally thinking that DNA is an extremely stable molecule, it actually turns out to be inherently unstable, constantly undergoing spontaneous changes and mutations. So how come it doesn’t simply disintegrate into chemical chaos?

The study was done by three people named Tomas Lindahl, Paul Modrich and Aziz Sancar.The answer lies in DNA repair mechanisms. Tomas Lindahl first demonstrated that DNA decays at such a rapid rate that development of life on Earth should have been impossible. This led him to look into how this collapse of DNA is prevented, and he discovered one such mechanism: base excision repair. When part of the DNA strand mutates, or spontaneously changes, a specific enzyme discovers this defect and “cuts” the damage out of the strand. Further enzymes then join in the action, filling in the gap with the original, correct sequence.

Mutations can also occur as cells are dividing, a process that requires copying the DNA for each new cell. This process is not error-proof, and mistakes can be made along the way, like adding in an incorrect building block, or base, that doesn't match up with the one on its partner strand (remember DNA is a double helix). Paul Modrich looked into how such mistakes are prevented during cell division, and described a mechanism called mismatch repair. This process, which also involves snipping out part of the DNA and replacing it, reduces the error frequency during DNA replication 1000-fold.

        The nucleotide excision repair, the mechanism that cells use to repair UV damage to DNA. People born with defects in this repair sstem will develop skin cancer if they are exposed to sunlight. The cell also utilises nucleotide excision repair to correct defects caused by mutagenic substances, among other things.
Another source of DNA damage is from external factors. One example is the damage that UV radiation does to our DNA, and Aziz Sancar mapped the mechanism that exists to repair this damage, called nucleotide excision repair. When a stretch, rather than a single site, of DNA has been corrupted by UV radiation, the enzymes involved in this mechanism come along and remove a large piece of the DNA containing the fault. The resulting gap then gets filled back in. People who are born with defects in this particular mechanism develop skin cancer if exposed to sunlight.

The mechanisms described by these Nobel Laureates have given us a fundamental insight into how cells function and repair themselves, as well as giving new targets for the development of new cancer treatments.   

REF: iflscience.com, thehindu.com