DNA Damage and Repair
Genotoxins
 Polonium is five million times more toxic than hydrogen cyanide and a single gram can self-heat to 500 oC. Unsurprising then that Alexander Litvinenko died very shortly after ingesting an unknown quantity of this radioactive element. Half a century ago Marie and Pierre Curie's daughter was accidentally exposed when a sealed capsule of polonium exploded on her lab bench. A decade later she died of leukaemia. On a broader scale this genotoxin has been ingested by those smoking tobacco grown using phosphate fertilisers.
However, the particles emitted during alpha-decay of polonium only wreak havoc in body tissues if ingested. In contrast, beta and gamma radiation are more severe and act across much greater distances, as has been apparent in the aftermath of nuclear tragedies such as Hiroshima and Chernobyl. Ionizing radiation snaps the DNA backbone as easily as we might break a hair. One break is sufficient to kill a cell.
Genotoxins are all around us and they don't just come from dangerous radioactive chemicals. Cosmic rays from outer space and UV from sunlight are absorbed by cells, causing cross-linking between complementary strands of DNA, which hampers replication. The oxygen that fills our lungs every few seconds helps us to metabolise food, but produces chemicals like hydrogen peroxide that can cause DNA damage. Car exhaust fumes spew forth a complex cocktail of hydrocarbons that fuel a huge diversity of biochemical alterations to our chromosomes.
Natural defence
Given the 3 billion base pairs present in every copy of your genome, it is a small wonder that the battery of daily assaults on a single cell, let alone the billions of cells in our body, don't cause more damage. For this, we are indebted to the evolutionary process that has graced us with a sophisticated DNA repair system. Even bacteria have a natural armoury to protect against insults to their genes.
So how does a cell know it has been assaulted? Are there sentinels on duty day and night to keep attackers at bay? The cell employs both signalling networks and DNA repair pathways, each comprised of around ten to twenty proteins. These pathways do not exist in isolation, but overlap on many levels with a host of shared players. Depending on the extent of the damage, the cell has to decide whether to repair the fault, ignore it and risk mutation, or bin itself to forego any ill-effects on the whole organism.
The components involved in such decisions will vary according to the way in which the genome has been damaged, who it belongs to and its overall stability. Take for example the marvellous Deinococcus radiodurans --- literally the 'strange berry that withstands radiation'--- discovered by accident around 50 years ago, during an attempt to sterilise tins of meat with gamma-radiation. This hardy bacterium evaded nuclear blasting, living to tell the tale by spoiling the meat.
'Conan the bacterium' has extremely fast acting DNA repair machinery and multiple copies of the genome in its single-celled body. The latter strategy affords it a useful way in which to re-synthesise DNA in the event of backbone breakage. Should part of the genome be lost in this way, the duplicate copies act as templates for its reconstruction. Versions of the players in the bacterial repair response have been found in yeast, mice and humans. For example, bacterial RecA -a repair protein - is very similar in sequence and function to yeast and human RAD51.
Breaks in the DNA backbone are picked up by 'checkpoint' proteins, which sit at the top of complex signalling cascades that hail repair troops to the damage site. ATM is one such 'caretaker of the genome' in humans. When it spots a double-strand snip in DNA, it acts as a loudspeaker activating other proteins to initiate one of two possible repair responses: homologous recombination (HR) or non-homologous end-joining (NHEJ).
HR is jolted into action when a single-strand of the DNA double-helix is severed, but if both strands snap, NHEJ kicks in too. Steve Jackson (Cancer Research UK Laboratories, Cambridge UK) works on the latter pathway. When double-strand breaks are generated, "Ku proteins jump onto broken ends" he explains. "These ring-shaped molecular policemen clamp the ends," allowing other proteins called ligases to 'glue' them together again.
If a single strand of the double-helix breaks, HR is triggered. Steve West (Cancer Research UK, Herfordshire UK) has identified a number of important components of this pathway, including a host of RAD proteins. When a cell is exposed to ionising radiation, RAD proteins rally together, visibly clumping at damage sites in the cell nucleus. RAD51picks up the broken end and searches for a complementary base-sequence. Once a suitable template is located DNA polymerases can do the job of re-synthesising damaged strands.
The EU is supporting research into this area through the DNA Repair Integrated Programme which is already making strides along new therapeutic avenues Kudos pharmaceuticals, DNage). We are also likely to benefit through caretaker strategies such as are offered by the fast-growing nutraceuticals industry. Antioxidants, although convincing data are still forthcoming, look like pretty good candidates for mopping up DNA-damaging chemicals we produce as by-products of normal metabolism.
Radioactive genotoxins might be rare, but internal genotoxic stress is a daily reality. A healthy DNA repair system protects us from all sorts of ills, whether caused by deliberate or accidental damage, including cancers and leukaemia (see DNA repair and cancer), premature ageing (see DNA repair and ageing) immune deficiencies, neurodegenerative diseases like Alzheimer's, certain cardiovascular disorders, diabetes and many other ageing-related disorders. The importance of DNA repair is highlighted by the existence of a number of rare inherited DNA repair defects that cause early death (see DNA repair and human disorders). Understanding more about our DNA repair systems and how to support these will therefore have great implications for health and disease.
Text by Brona McVittie, Science Writer, London, UK. | Figure: The power of polonium (source).
| 
