Our bodies take an immense amount of beating on a day-to-day basis. The environment is full of toxins that affect our cells. From ambient radiation to the food we eat, these toxins sometimes have a direct effect on our cells and the DNA that lies within them. So how is our DNA protected from these external stresses? This question formed the basis of my PhD work!
It turns out that within our cells there are proteins that serve as the guardian angels of the DNA. The proteins, known as DNA repair proteins, are able to sense and repair any damage they encounter in the DNA. Their functions are extremely specialized and the protein workload is astonishingly distributed to eventually repair the damaged DNA lesions. Damage sensors first sense the damaged DNA. They then recruit adaptors, which serve as platforms for the effectors. The effectors are mostly enzymes, which degrade the damage and replenish the site with good DNA.
The repair of a damaged site is not dissimilar to the repair of say a railway track, or a damaged building! The damage is sensed by the maintenance guys and then eventually repaired by workers specialized in replacing specific components of the site.
During my thesis, I worked on an adaptor protein very similar to its more famous counter parts BRCA1 and BRCA2. BRCA1 and BRCA2 are key proteins implicated in breast cancer. This family of proteins contains a signature region, which allows them to build a scaffold around the site of damage. This scaffold serves as a solid platform that can then be used by the effector proteins to repair the site. It is indeed quite remarkable that all this is going on inside our cells!
But how does this really work?
Take a scenario where a building’s caught fire. The fire alarms sense it the fire, which then brings the fire brigade to the site. Once the fire has been contained, calls are made to the construction workers who build the scaffolds and rebuild the structure, after which the plumbers, electricians and so on eventually work together to repair the building. In cells, these signals are transmitted from protein to protein by subtle biochemical modifications.
In my case, I was able to figure out that a sensor protein could transmit a signal to an adaptor protein by tagging it with a phosphate group. These DNA repairmen use this kind of signal commonly. What the phosphate group does is increase the negative charge of the protein, thereby allowing it to change its structure. In some cases, this turns a protein on and in some cases it turns it off! It’s a simple mechanism that works extremely efficiently.
In this case, I found out that the negative charge turns my protein on and allows it to move to the vicinity of the damaged site, where it serves as a platform for the effectors! I was able to show that in the absence of this guy, cells were unable to repair these damaged sites.
You can’t really repair a building without a scaffold!
- Ullal P1, Vilella-Mitjana F, Jarmuz A, Aragón L. Rtt107 phosphorylation promotes localisation to DNA double-stranded breaks (DSBs) and recombinational repair between sister chromatids. PLoS One. 2011;6(5):e20152. PMID: 21647453.