Definition of Xeroderma Pigmentosum: XP

•XP, first described in 1874, is a rare genetic defect in the nucleotide excision repair mechanism. It is characterized by hypersensitivity to the ultraviolet portion of sunlight.

Symptoms of XP:

• increased skin and eye cancers

• early onset of freckling

• blistering with minimal sun exposure

• blindness and deafness

• dwarfism and hypergonadism

• mental retardation

Basic Statistics on XP:

• XP is an autosomal recessive disease • XP patients are 1000 times as susceptible to sunlight induced skin cancers• About 1 person in 100,000 has the disease• It effects both young and old, although the disease is usually diagnosed at a very early age.

Skin Cancer Rates in XP Patients

CANCER ETIOLOGY

DNA damage causes mutations that activate oncogenes or

inactivate tumor suppressor genes.

Oncogenes

• Growth factor receptors

• Protein tyrosine kinases (e.g., ras and src)

• Transcription factors (e.g., Fos, Jun, Myc)

Tumor suppressor genes

•Cell cycle control and apoptosis

•p53 (“guardian of the cell”)

•p21 and p16 (CDK inhibitors)

•Rb (negative regulator of E2F)

•DNA repair

XP is characterized by an inability of a cell to repair damage caused by UV leading to genetic instability and skin cancer.

Nucleotide Excision Repair or (NER)

This system is responsible for removing the damaged segments of DNA and restoring the original sequence of DNA.

The NER mechanism is composed of two types: global genome (GGR) and transcription coupled (TCR)

Seven XP genes are central to NER which includes many other accessory proteins.

Complementation Groups for XP:

XPAXPBXPCXPDXPEXPFXPG

DNA damage recognition:

• XPA and XPC are both damage-recognition proteins and are considered the “classical” forms of XP.

• (XPE is probably also involved in damage recognition)

Current Model for Mammalian NER

DNA damage accessibility :

XPB and XPD are topoisomerases that unwind the damaged region of DNA. They are components of the general transcription factor TFIIH. Defects in XPB or XPD lead to the developmental and neurological symptoms of XP (e.g., dwarfism, hypogonadism, etc.)

Current Model for Mammalian NER

DNA incision enzymes:

XP-F and XP-G are responsible for making incisions at either side of the damage, leading to the release of a 29 base fragment including the damaged bases.

Current Model for Mammalian NER

Evidence supporting UVB damage to XPA repair gene:

• A group of scientist at the University of Utrecht , The Netherlands did an experiment involving transgenic mice in which the XPA gene had been “knocked out.”. The three groups of mice they studied had functional XPA (XPA +/+), were heterozygous for XPA ( XPA +/-), or had nonfunctional XPA ( XPA -/-) .

•The purpose of the experiment was to compare the effects of UVB light and carcinogen exposure in the three different groups.

Effects on the Embryonic stage of development:

•Problems began to develop with the XPA -/- genotype 13 days after conception. These included

- growth retardation- decreased liver size- embryonic anemia, resulting in a 50% mortality rate.

•In both XPA +/+ and XPA+/- there were no abnormalities observed in this stage of development.

Postnatal effects:

• All three genotypes of XPA developed very similarly until they reached 13 months old.

• At this time primary fibroblasts were taken from each mouse group and exposed to 4 Jm -2 of UVB light.

• The XPA -/- cells had a 90% mortality rate.• Both the XPA +/+ and XPA +/- genotypes suffered no losses to exposure to UVB light.

•These results are very similar to those found in cells isolated from XP patients.

UV carcinogenesis protocol:

•To test the mice’s susceptibility to skin cancer all three genotypes were exposed to one (1) low daily dose of UVB light which gradually increased to 310 Jm-2 for a total of eight weeks.

Effects of UVB on skin cancer:

After one week of exposure to UVB light :

• XPA +/+ and XPA +/- mice showed no external signs of exposure• XPA -/- mice showed hyperkeratosis and necrosis on exposed dorsal areas of the skin

Effects of UVB on skin cancer:

Six weeks into the experiment the evidence of damage became more evident in XPA -/-.

• Abnormalities in the eyes were observed in the XPA-/- knockouts, but not in the normal or heterozygous mice.

Effects of UVB on skin cancer:

• The UVB exposure was discontinued after 14 weeks due to the overwhelming presence of Bowenoid lesions found in the eyes of the XPA-/- mice.

• It was at this time that the first cancers were noticed in the XPA-/- mice.

•75% of the XPA -/- mice developed at least one squamous cell carcinoma by week 25.• No cancers were observed in the other two phenotypes

Experimental Results:

Mice with a defect in the XPA gene (XPA -/- ) and defective in NER strongly mimic the phenotype of XP patients. These mice have become very important tools for understanding the molecular biology of skin cancer and developing strategies for its prevention.

Conclusion :

XP is a hidden disease that robs its hosts of their freedom. It also is a disease that begins to effect a person at a very young age. Further XP research is necessary and important if we are to eliminate this degenerative disease.

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