Muscular dystrophy. Sickle-cell anemia. Huntington's disease. These are just a few of the thousands of genetic disorders that afflict millions and can often be very difficult to treat. Sometimes the underlying DNA mutation of one of these disorders may be inherited, but other times these mutations can happen because of any number of environmental or cellular processes.
The human genetic code is organized into 24 chromosomes. Unravel a chromosome and you will find what Doctors Watson and Crick did, a tightly-packed double helix of DNA – two strands of nucleotides joined together by hydrogen bonds – RNA, and proteins. Nucleotides on each strand pair off in what are called base pairs, adenine (A) with thymine (T) and cytosine (C) with guanine (G). Two of the chromosomes are called the sex chromosomes: women have two X chromosomes while men have one X and one Y chromosomes. Many X-recessive genetic disorders, like hemophilia, are much more prevalent in men because they lack a backup X chromosome. The other 22 chromosomes are called autosomal and come in pairs of two, one maternal and one paternal copy.
What Causes DNA Mutations?
Some of the factors involved in producing DNA mutations are environmental, such as radiation or mutagenic chemicals. Even cells' regular metabolic activity can cause them. Take, for instance, the free oxygen radicals produced during cellular respiration in the mitochondria. These molecules can unravel proteins and other cellular components. Sometimes, mutations can happen when DNA is copied incorrectly, like during preparation for cell division or when translated into messenger RNA (mRNA), the courier molecule that takes gene blueprints to ribosomes, cells' protein factories.
Damage to DNA can be as seemingly insignificant as one half of a base pair being defective, a C being where a T should be. This can cause a single-strand break (SSB), tens of thousands of which take place every day in every cell. More devastating, but also less frequent, are double-strand breaks (DSB), where the double helix is at risk of structural disintegration. Other possible damage scenarios exist, but these are two main ones recognized in the scientific literature.
When damage does occur to a piece of DNA, special proteins congregate at the damage sites to signal the DNA repair pathways. One of these proteins, histone H2AX, phosphorylates and flanks the lesion site. Once enough of these proteins and markers have appeared, the DNA repair mechanisms get to work.
How Cells Repair DNA
Here are listed the four primary mechanisms of a cell's DNA repair pathway, as described in a Journal of Cellular Physiology article:
- BER (base excision repair) is for damage involving just a single base pair, a single-strand break scenario. This involves several enzymes whose jobs include detecting the damaged base, removing it, recognizing what the correct nucleotide is, and then "gluing" it in.
- NER (nuclear excision repair) is for more serious SSB damage, between two and 30 bases long. NER can repair in two ways. Global genome repair (GGR), is a slow-moving, exhaustive check of entire chromosomes. NER's other setting is transcription-coupled repair (TCR), a rapid repair mechanism that only removes damage from active genes and only from the strand that is going to be transcribed into mRNA, on the way to becoming a protein.
- HR (homologous recombination) is a more sophisticated repair mechanism that deals with double-strand breaks. It compares the damaged site to its counterpart on the undamaged homologous chromosome – remember, each parent provides an offspring one copy of each chromosome – and uses the latter as a template to fix the double-strand break.
- NHEJ (non-homologous end-joining) is more crude. It simply rejoins the two ends were the DNA frayed, overlooking the possibility that some base pairs may have been lost when the double-helix broke.
Stem Cells and DNA Repair
Recent research involving DNA repair and stem cells has led many to believe that certain types of cells may rely more on some DNA repair mechanisms than others. For example, the global genome repair (GGR) approach of nuclear excision repair (NER) favors detail over speed, indicating that it may be especially important in [embryonic] stem cells. Because stem cells have the potential to differentiate into any cell type in the human body, to repopulate an entire body in the case of embryonic stem cells, they need to carefully monitor and maintain their entire genomes. Any mutations in a stem cell's DNA could be passed when that cell proliferates and differentiates.
NER's other setting, transcription-coupled repair (TCR), only repairs damage to active genes, as described above. This method is thought to be most common in somatic cells, those cells already differentiated into a specific type or tissue (e.g. heart muscle or neuronal). After all, why should a muscle cell care about fixing genes related to neural activity or blood hemoglobin since it will never be anything but a muscle cell?
Gene Therapy
Presently gene therapies are still in their infancy. But there is a growing body of research out there trying to harness the ability to identify mutations and damage to DNA, repair it, and if possible make sure that no future cells inherit the faulty nucleotide bases or genes. One day these gene therapy may prove revolutionary in treating genetic disorders, but continued research and clinical trials are required before such therapies are deemed safe.
References:
Simonatto M, et al. "DNA Damage and Cellular Differentiation: More Questions than Responses." Journal of Cellular Physiology 213: 642-648, 2007. doi:10.1002/JCP.
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