Defects in DNA Repair and Resulting Diseases

DNA Damage Makes Cells Vulnerable to a Number of Serious Problems

Aug 10, 2009 Philip McIntosh

DNA, the genetic material in cells, undergoes many repair operations every day. Defects in the repair system can result in permanent DNA damage leading to disease.

Cells use specific proteins to detect and repair DNA damage. Damage arises from exposure to electromagnetic or nuclear radiation, certain chemicals, or just by chance. In normal cells, limited forms of damage can be repaired quite efficiently.

Damage to DNA occurs when the base pairing rules are violated. Although the DNA bases, which hold the genetic code in their sequence, can be in any order on a DNA molecule, certain rules govern which bases can appear across from each other along a double-stranded DNA molecule. According to Chargaff's base pairing rules, the four bases—adenine (A), cytosine (C), guanine (G) and Thymine (T)—can exist across from each other only in the pairs AT and CG.

In addition to improper base pairing, DNA damage results when a base becomes improperly linked to another base next to it. This type of defect is particularly common when two T's next to each other (not across from each other) along a DNA strand become cross-linked to form a thymine dimer.

DNA Repair Proteins

DNA repair is accomplished by systems of proteins (enzymes). Specific proteins physically check DNA for altered bases or bases that improperly cross-link to each other. These proteins interact directly with DNA by binding to it. They detect damage by mechanically sensing changes in shape. If a base pairing is incorrect (for example a C across from a T, instead of a G) the conformation of the DNA is altered, creating bulges or kinks, which are sensed by the repair proteins.

Repair is made by removing and replacing defective bases. When damage is detected, the molecular repair machinery excises a short sequence of bases on one side of the DNA strand. The removed sequence of bases is then resynthesized according to the base pairing rules specified by the unexcized side of the strand.

Xeroderma Pigmentosum

Xeroderma pigmentosum (XP) results from defects in one of seven genes (XPA-XPG) important in repairing DNA damage caused by ultraviolet (UV) light. The disease results when both parents are carriers of the defect and each contributes their mutation to a child. The disease exists from birth. As is true of all recessive genetic disorders, a single copy of the defective gene is insufficient to cause the affliction.

Ultraviolet rays frequently rearrange the electrons in adjacent thymine bases, causing them to cross-link together. This type of damage occurs in skin cells every time they are exposed to sunlight. If left unrepaired, or repaired improperly, whatever proteins are coded for by the damaged sequence can malfunction.

XP patients are at high risk for skin cancer and must be protected from the sun and other sources of UV radiation. With great caution in sun exposure, XP patients can live to middle age.

Trichothiodystrophy

Trichothiodystrophy is caused by defects resulting in reduced RNA transcription of specific proteins. About half of all cases of trichothiodystrophy exhibit photosensitivity associated with some of the same DNA repair genes implicated in XP.

Symptoms include brittle hair and nails, scaly skin, and physical and mental deficiency, protruding ears and receding chin. The symptoms are thought to result from an overall low level of RNA transcription. Sufferers look prematurely aged, because of a lack of subcutaneous fat under the facial skin.

The name is indicative of the fact that hair (tricho) lacks sulfur (thio)-containing proteins. Early death is common, but rarely a patient may live to middle age.

Cockayne Syndrome

Cockayne syndrome sufferers are sensitive to sunlight, are short, and appear prematurely aged. The disease results from an inability to repair DNA damage detected during transcription. The risk of cancer does not seem to be increased, unless the XP defect is also present. Two genes coding for DNA repair proteins are implicated and the disease only results if there are two defective copies of the same gene.

The disease manifests in three forms (with or sometimes without the symptoms of XP). Type I disease is not evident at birth, but progresses to symptoms at around the age of one. Type II disease is evident at birth. The rarer and less severe Type III occurs later in life. Life span is correlated with onset, with earlier onset (Type II) resulting in the shortest predicted life span.

Treatment of DNA Repair Diseases

There are no cures for diseases caused by defective DNA repair. Treatment of specific symptoms, and protection from exposure to UV light are usually the only options. In the case of XP, application of good versions of the defective proteins in a topical cream is undergoing testing. Someday, it may be possible to repair the underlying genetic defects using gene therapy.

References

Xeroderma Pigmentosum Society

Trichothiodystrophy Information

Cochayne Syndrome Information

The copyright of the article Defects in DNA Repair and Resulting Diseases in General Medicine is owned by Philip McIntosh. Permission to republish Defects in DNA Repair and Resulting Diseases in print or online must be granted by the author in writing.

Artist's Representation of DNA

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