Sunday, April 22, 2007

Nonhomologous End Joining

'DNA-Repair Machine Maintains Genomic Stability' is a good introductory article for DNA repair in general and, more specifically, for a type of repair known as nonhomologous end joining; often represented by the acronym NHEJ. There are two well known mechanisms by which the repair of DNA double-strand breaks are made. The already mentioned nonhomologous end joining being one and homologous recombination the other. As the article states:

"The fidelity of the genome is under constant threat — toxic chemicals, ionizing radiation, even the byproducts of normal cellular metabolism can wreak havoc on DNA. In some instances, DNA damage is severe enough to chop the double helix in two. When this happens, a group of proteins that fixes double-stranded DNA breaks mobilizes to make repairs. If a break goes unfixed, the consequences to the cell can be disastrous, ranging from wholesale gene rearrangements to massive chromosomal breakdown."

Note that the causes of DNA damage are everywhere and exist at all times. Even normal cellular metabolic activities can engender damage to an organism's genome. Repair mechanisms are not a luxury. They are vital to the ability of organisms to maintain vital functions and stave off cancer. Compromising the effectiveness of DNA repair functions can be fatal to an organism. More from the same article:

"In an experiment designed to assess the role of the NHEJ pathway in repairing general chromosomal damage induced by radiation, the scientists irradiated fibroblast cells that were deficient in both Lig4 and p53, a key DNA damage sensor. Normally, p53 prevents damaged cells from proceeding in the cell division cycle."

Repair mechanisms are irreducibly complex in that they are composed of multiple proteins and their encoding genes. There are also many different types of repairs. Yet we repeatedly witness the disabling of a single protein in one of the repair pathways as sufficient to cause fatal diseases. A viable evolutionary process would require effective repair mechanisms very early in the history of life. In my view this means the very begining of life itself. The problem caused by an absence or incomplete set of repair mechanisms is an inability to retain beneficial encoding information within an organism's DNA. This also makes problematic the capacity to generate increases in genomic information that would accompany any selected changes. If information is lost faster than it can be incremented, the demise of affected organisms is an inevitable result.



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