Download No Slide Title

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:
XPA
XPB
XPC
XPD
XPE
XPF
XPG
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.
Are there any Questions ?