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Perhaps the worst fate to befall a chromosome is to be completely severed. In the DNA repair business, this is simply called a double strand break. If left untreated, the best case scenario is probably death of the parent cell via programmed suicide. If the break isn’t even detected, the cell can go on to form a cancer that spreads as a clone throughout the body until either you or it is eradicated.

In the worst case — at least evolutionarily speaking — the break can occur in a germ cell, in which case the damage can potentially persist even when you are long gone. Fortunately, in most cases the cell not only detects the break, but repairs it more cleanly than you can patch a tire. The full mechanism is still a bit mysterious. However, recent work now indicates that special DNA binding proteins known as histones are the first line of defense.

A paper just published inNature Chemical Biology has identified the various molecular ‘reader’ marks and accessory proteins that recruit a specific histone variant known as H2AX to the damage hotspot. Before getting in to all of that in more detail, we should probably take a step back and talk a bit more generally about what histones normally do.

The lowest order structure of our chromosomes, the so-called nucleosome, is basically a length of DNA wound on an octet core made from two copies of each of the four core histone proteins (H2A, H2B, H3 and H4). To complicate matters, histone H2A is actually a large class of different proteins mined from different genes. The only histone thus far implicated in repair is a variant form (H2AX) that has an extra amino acid tail appended to it.

It was previously known that when chromosomes are broken as a result of radiation or toxic chemical assaults, H2AX is given a special phosphate tag on one of its serine residues. This kind of phosphorylation occurs all the time on many other kinds of proteins, but histones are more typically associated with those modifications shown above, namely acetylation and methylation. Lest you get the idea that a single copy of phosphorylated H2AX is enough to carry out the entire repair program, several hundred or even thousands of copies of H2Ax are actually activated in this way by a single break.

The key insight here is that after H2AX gets phosphorylated, you need to call it by its proper name: γH2AX. I say that only half jokingly. The name of the game in repair today is little more than a lengthy annotated list of who is wearing what, and who dating who in the molecular world. Its kind of like when you go to the mechanic and ask “whats wrong” — you just get a list of parts that need to be bolted on to the other parts, rather than a description of how cars really run and fail. No real worries though; that should all come in time.

Anyway, once this γH2AX has been vested with its phosphate accessory, it is free to bind several other players, including the likes of none other than 53BP1. As the authors show, when this particular molecule uses its own BRCT domain to recognize its partner, they fit together like a hand and glove. Then, somehow, through unseen Brownian wonder the repair just happens. The actual known details involve some pretty fancy footwork that has names like ‘homologous recombination’ and ‘strand annealing,’ but that is probably a subject for another time.

There is some method to the madness we have described here, and we are not in completely unfamiliar territory when we appear to just throw out acronyms like BRCT to our unsuspecting audience. Some with personal experience may even recognize it as the BRC or ‘Breast Cancer’ terminal domain of the breast cancer DNA-repair protein of the same name, which incidentally may have some similar functionality to our H2AX.

Not so long ago ownership of this pivotal BRCA1 gene by Myriad Genetics was the subject of one the largest patent wars in the biomedical field. Fortunately, these days the question of who owns which of the molecules of life we share in common seems to have taken a backseat to who owns which of the man-made molecules that may target them for possible treatments.