Abstract
Human XPA is a protein engaged in DNA damage recognition and repair. A mutation in the gene encoding the protein causes an autosomal recessive disorder, xeroderma pigmentosum (XP), which renders an individual sensitive to sunlight and causes skin cancer. XPA is a 273 amino acid protein, which is predominantly localized in the nucleus. It is expressed at both high and moderate levels in several tissues. The protein serves as a damage sensor in a nucleotide excision repair mechanism, through which the damage to a DNA strand is verified and repaired by formation of a newly synthesized strand. Besides this primary NER mechanism, XPA in conjunction with other XP proteins participates in many non-NER pathways and interacts with other proteins, to maintain the genome integrity.
Xeroderma pigmentosum, complementation group A or XPA is a protein involved in the DNA damage recognition and its repair. DNA is often subjected to damage due to UV rays from the sun and by toxic chemicals, radiation and free radicals and carcinogens. Normally, cells are able to employ a mechanism called nucleotide excision repair (NER). As a part of this mechanism, XPA recognizes the damage and repairs it by stabilizing the DNA. XPA binds to the stretches of damages DNA and binds to other proteins to form a complex, which unwinds that region of the damaged DNA, excises it and corrects the damaged area with a new strand of DNA. The specific function of XPA is to verify that the proteins are held in place, before the nucleases excise the damaged DNA. XPA protein associates with other proteins such as ERCC1, ERCC4 to form a ternary complex, which is involved in the damage recognition and incision activities . The interaction between XPA and ERCC1 has been demonstrated to be mandatory in the NER pathway and the potential role of the interaction is to employ the ERCC1 incision complex to the site of damage.
XPA is a 273- amino acid protein and has a molecular weight of 31 KD. It contains alpha-helices and zinc-finger motifs, characteristic of other DNA binding protein. It is expressed in about 55 of 78 normal tissue cell types at high or medium concentrations . High expression of human XPA is observed in tissues like gall bladder, pancreas, tissues of the digestive tract like oral mucosa, esophagus, stomach, appendix, colon, urinary bladder and reproductive tissues such as the epididymis, prostate, seminal vesicle, vagina endometrium. Liver, bile ducts and kidney glomeruli exhibit negligible levels of the protein. XPA is primarily located in the nucleus, although it is found in the cytoplasm and Golgi apparatus as well.
The gene encoding XPA is located at chromosome 9q34.1 . A mutation in the gene encoding XPA causes an inherited disease called xeroderma pigmentosum (XP) . It is an autosomal recessive genetic disorder in which the DNA damage repair is defunct, which eventually makes an individual highly sensitive to sunlight, changes in the pigment and increases the occurrence of skin cancer. Patients that do not exhibit sensitivity to sunlight, sometimes show freckle-like pigmentation caused due to the high number of melanocytes on skin regions exposed to sunlight. This may even lead to skin cancers, if the skin is not protected from sunlight as well as neurological problems. Several deletion and insertion mutations have been identified in the patients with this disorder. Patients with more severe form of the disease and more complicated neurological symptoms displayed mutations in the DNA-binding region of XPA, whereas patients with only a mild skin disease exhibited mutations in the C terminal end of the protein, which interacts with the TFIIH transcription factor . A study has reported both homozygous and heterozygous mutations in the XPA gene. A mutation analysis on cell lines obtained from 19 American and European patients revealed deletions and splice site mutations in exonic regions of XPA, which resulted in frame shifts in the DNA-binding region. Point mutations or missense mutations in the DNA-binding region on XPA are rare, suggesting that patients are intolerant to minor amino acid changes in the DNA, hence causing mild symptoms and escape detection .
In their study, Shell et.al describe the non-NER pathways and protein-protein interactions involved in the process of recognition and recruitment of DNA damage repair factors, elimination of the damaged DNA strand and regeneration of the new strand . XPA functions as a damage sensor and interacts with cell-cycle arrest kinase ATR and GTPase XAB1 which facilitate its translocation of XPA from the cytoplasm into the nucleus, single strand DNA binding protein, RPA, transcription/ repair complex TFIIH, GTPase XAB1, protein active in mRNA splicing XAB2, and endonuclease XPF. Thus, besides the core NER pathway, XPA and other XP proteins are engaged in non- NER mechanism, such as formation of pre-incision bubble structures, which contribute to the genome repair and stability in response to UV, carcinogens and other environmental factors causing DNA damage.
REFERENCES
Lehmann, A. (2011). Xeroderma pigmentosum. Orphanet Journal of rare diseases, 6: (70).
OMIM.org. (n.d.). Retrieved from http://omim.org/entry/611153
Shell, S. (2008). Other Proteins Interacting with XP Proteins. Advances in Experimental Medicine and Biology, 637: 103-112.
The human Protein Atlas. (n.d.). Retrieved from Proteinatlas.org: http://www.proteinatlas.org/ENSG00000136936-XPA/tissue
