The XPD (ERCC2) gene encodes for a 2.3-kb mRNA containing 22 exons and 21 introns. The XPD protein is a 760 amino acids polypeptide with a size of 87kDa. Defects in this gene can result in three different disorders: the cancer-prone syndrome xeroderma pigmentosum complementation group D, photosensitive trichothiodystrophy, and Cockayne syndrome.[1]
Just like XPB, XPD is also a part of human transcriptional initiation factorTFIIH and has ATP-dependent helicase activity.[2] It belongs to the RAD3/XPD subfamily of helicases.
XPD is essential for the viability of cells. Deletion of XPD in mice is embryonic lethal.
Consequences of mutations in ERCC2
The ERCC2/XPD protein participates in nucleotide excision repair (NER), and is employed in unwinding the DNA double helix after damage is initially recognized. NER is a multi-step pathway that removes a wide range of different damages that distort normal base pairing. Such damages include bulky chemical adducts, UV-induced pyrimidine dimers, and several forms of oxidative damage. Mutations in the ERCC2/XPD gene can lead to various syndromes, either xeroderma pigmentosum (XP), trichothiodystrophy (TTD) or a combination of XP and TTD (XPTTD), or a combination of XP and Cockayne syndrome (XPCS).[3] TTD and CS both display features of premature aging. These features may include sensorineural deafness, retinal degeneration, white matter hypomethylation, central nervous system calcification, reduced stature, and cachexia (loss of subcutaneous fat tissue).[3][4] XPCS and TTD fibroblasts from ERCC2/XPD mutant human and mouse show evidence of defective repair of oxidative DNA damages that may underlie the segmental progeroid (premature aging) symptoms[5] (see DNA damage theory of aging).
↑ 3.03.1Andressoo JO, Hoeijmakers JH, Mitchell JR (2006). "Nucleotide excision repair disorders and the balance between cancer and aging". Cell Cycle. 5 (24): 2886–8. doi:10.4161/cc.5.24.3565. PMID17172862.
↑Andressoo JO, Mitchell JR, de Wit J, Hoogstraten D, Volker M, Toussaint W, Speksnijder E, Beems RB, van Steeg H, Jans J, de Zeeuw CI, Jaspers NG, Raams A, Lehmann AR, Vermeulen W, Hoeijmakers JH, van der Horst GT (2006). "An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria". Cancer Cell. 10 (2): 121–32. doi:10.1016/j.ccr.2006.05.027. PMID16904611.
↑ 6.06.1Iyer N, Reagan MS, Wu KJ, Canagarajah B, Friedberg EC (Feb 1996). "Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein". Biochemistry. 35 (7): 2157–67. doi:10.1021/bi9524124. PMID8652557.
↑ 7.07.1Drapkin R, Reardon JT, Ansari A, Huang JC, Zawel L, Ahn K, Sancar A, Reinberg D (Apr 1994). "Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II". Nature. 368 (6473): 769–72. doi:10.1038/368769a0. PMID8152490.
↑Coin F, Marinoni JC, Rodolfo C, Fribourg S, Pedrini AM, Egly JM (Oct 1998). "Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH". Nature Genetics. 20 (2): 184–8. doi:10.1038/2491. PMID9771713.
↑Vermeulen W, Bergmann E, Auriol J, Rademakers S, Frit P, Appeldoorn E, Hoeijmakers JH, Egly JM (Nov 2000). "Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder". Nature Genetics. 26 (3): 307–13. doi:10.1038/81603. PMID11062469.
↑Giglia-Mari G, Coin F, Ranish JA, Hoogstraten D, Theil A, Wijgers N, Jaspers NG, Raams A, Argentini M, van der Spek PJ, Botta E, Stefanini M, Egly JM, Aebersold R, Hoeijmakers JH, Vermeulen W (Jul 2004). "A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A". Nature Genetics. 36 (7): 714–9. doi:10.1038/ng1387. PMID15220921.
Jeang KT (1998). "Tat, Tat-associated kinase, and transcription". Journal of Biomedical Science. 5 (1): 24–7. doi:10.1007/BF02253352. PMID9570510.
Yankulov K, Bentley D (Jun 1998). "Transcriptional control: Tat cofactors and transcriptional elongation". Current Biology. 8 (13): R447–9. doi:10.1016/S0960-9822(98)70289-1. PMID9651670.
Lehmann AR (Jan 2001). "The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases". Genes & Development. 15 (1): 15–23. doi:10.1101/gad.859501. PMID11156600.
Benhamou S, Sarasin A (Nov 2002). "ERCC2/XPD gene polymorphisms and cancer risk". Mutagenesis. 17 (6): 463–9. doi:10.1093/mutage/17.6.463. PMID12435843.
Clarkson SG, Wood RD (Sep 2005). "Polymorphisms in the human XPD (ERCC2) gene, DNA repair capacity and cancer susceptibility: an appraisal". DNA Repair. 4 (10): 1068–74. doi:10.1016/j.dnarep.2005.07.001. PMID16054878.
