Xeroderma Pigmentosum: An Autosomal Recessive Disorder

Discovered in 1884, the Xeroderma Pigmentosum (XP), an autosomal recessive disorder was discovered. It has a prevalence of 1-45 in a group of 45 million. It is variable in different It is distinguished by the patient's responsiveness and sensitivity to Ultraviolet light induced skin cancer. Patients with this disease are characterized by their defective DNA repair and are predisposed to cutaneous malignancies. The extensive research on the understanding of it's molecular etiology has promoted development of therapeutic approaches. The pathophysiology of XP includes deficient excision repair in XP skin fibroblasts, defective excision repair in XP cells, UV radiation hypersensitivity and heterogeneity of XP molecular defects.

Skin changes that occur include freckling of skin which is associated with pigmentation, telangiectasias, thin skin and skin cancers. The neurologic manifestations include impaired hearing, spasticity, areflexia, peripheral neuropathy and cognitive deterioration. Genes associated with XP take part in nucleotide excision reconstruction of DNA damage which is stimulated by carcinogens and UV. DNA is sensitive to damage which can be caused by intrinsic instability and environmental agents like chemicals.

Get quality help now

KarrieWrites

Verified writer

Proficient in: Disorder

5 (339)

“ KarrieWrites did such a phenomenal job on this assignment! He completed it prior to its deadline and was thorough and informative. ”

+84 relevant experts are online

Hire writer

Lesions occur along he DNA strand and they might lead to variations such as translocation and deletion. The alterations that can occur include structural conformations in the bases which compromise the replication of DNA particularly in the S phase and double strand breaks which may lead to translocation. In order to counteract the detrimental effects of the different types of DNA damage, DNA repair systems are formed.These systems include the Nucleotide Excision Repair (NER) and the Transcription-dependent damage recognition pathway.

Nucleotide Excision Repair (NER)NER is a DNA repair system that removes a wide range of base lesions that are produced on one strand. This comprises of pyrimidine (6-4) pyrimidone photoproduct (6-4PP), (UV) induced cyclobutane pyrimidine dimer (CPD) as well as substantial base adducts which are produced by a variety of chemical compounds. The lesions differ in chemical structure and they are supposed to reduce or increase the helical structure distortion of the DNA. NER defects are linked to a couple of autosomal recessive hereditary disorders. Most commonly known is the XP . Through cell fusion classical complementation analyses have recognized eight groups of complementation in XP whereby the participating genes are cloned. XP-A through XP-G are linked to deformed NER. A form of XP which is variant (XP-V) is significant in NER and inefficient in DNA polymerase ћ (pol ћ) that participates in translesion DNA synthesis.NER Mechanism And XP Gene ProductsBase lesion sensing and location identification occurs as the first step of the NER mechanism. Two different kinds of mechanisms take place in a parallel fashion. These include; Global Genome Repair (GGR) which works on any part of the genome and the transcription-coupled repair (TCR) which is designed to remove lesions from the active genes. The relevance of the GGR is observed in its ability to decrease the possibility of the replication forks for DNA to get lesions. This therefore thwarts gene mutations and aberrations. (XPC), one of the XP genes, that occurs as a heterotrimetric structure puts into code a basic protein (6,7). This protein is necessary for identification of damage in GGR (8-10) This protein consists of one of Saccharomyces cerevisiae Rad23p and centrin 2. Centrin 2 is a centrosomal protein that occurs in the calmodulin superfamily (11,12) and has been shown to heighten the XPC's damage recognition factor.The DNA binding activity is shown by XPC where a preference for a branched DNA is exhibited. The helical distortion that occurs as a result of unwinding is important for the identification by XP and NER machinery (25,26) so that DNA damage is not necessary for XPC binding if the DNA molecule contains an artificial form. XPC identifies single-strand configurations in the functioning strand facing the lesion (28). The efficiency of GGR differs among lesions in that 6-4PPs (33-34) which distort more are easily identified by the XPC as compared to the UV-induced CPDs that cause a minor helical distortion.Damage Recognition ProcessUV-damaged DNA binding protein (UV-DBB) was originally classified as a heterodimer and it has two subunits DDB1 and DDB2. DDB2 is linked to the XPE gene product (35-38). UV-DBB possesses an increased affinity for binding as opposed to XPC for specific lesion types, mostly UV associated lesions. In patients with XP-E there is severe impairment of CPD in fibroblast cells . UV-DBB relates with XPC through a UV irradiation process where UV-DBB facilitates the provision of XPC to UV-damaged locations. Besides that, UV-DBB displays affinity for bubble structures (49-51) , chemical agents and abasic sites. Cullin 4A , Roc 1 and the COP9 signalosome interacts with UV-DBB . Being a component of ubiquitin ligase (52) it seems to be stimulated upon UV treatment of cells. DDB2 and cullin 4A are polyubiquitylated . This degradation is UV induced. It is seen that UV-DBB is assisted by ubiquitylation to dissociate from the lesion thus allowing UV-DBB to be removed from the lesion.