XPD Helicase (3CRV)

XPD Helicase

Xeroderma pigmentosum group D (XPD) helicase is a subunit of Transcription Factor II Human (TFIIH), which aids in DNA repair. XPD helicse unwinds DNA, allowing other DNA repair enzymes to access and correct damaged regions in the DNA. Because the type of DNA damage that XPD helicase helps to fix is caused by UV light radiation, mutations in XPD helicase results in diseases characterized by light sensitivity.

Function

XPD helicase is an essential subunit, of the general transcription factor IIH (TFIIH), which is a complex that, along with other general transcription factors, help to initiate transcription and repair damaged DNA ^[1]. XPD helicase helps to stabilize the structure of TFIIH but also plays a functional role in repairing DNA as a helicase enzyme ^[2]. Helicases, of which XPD helicase is an example, are enzymes that unwind double-stranded DNA into single-stranded DNA so that other enzymes, like polymerases, can act upon the DNA ^[3]. In the context of DNA repair, helicases unwind DNA, and other enzymes remove the damaged DNA and replace it with the complementary nucleotides based on the other DNA sequence. When DNA is exposed to ultraviolet (UV) radiation, adjacent nucleotide bases, often thymines, can react and form bulky pyrimidine dimers, which can block enzymes that work on DNA ^[4]. For example, during DNA replication, thymine dimers do not fit into the active site of DNA polymerases smoothly, sometimes resulting in mismatched nucleotides. To fix this type of damage on single strands of DNA, cells employ a process called nucleotide excision repair (NER) ^[2]. This is the type of DNA repair that TFIIH, with the help of the XPD helicase subunit, carries out to remove the damaged DNA.

Breaking the hydrogen bonds that hold the two DNA strands together requires energy, so XPD helicase is dependent on ATP ^[5]. The ATP-dependent helicase activity of XPD helicase, however, is only required for NER, even though TFIIH participates in both repair and transcription initiation ^[6]. XPD helicase not only unravels the DNA around the damage but also helps TFIIH in recognizing bulky lesions in DNA ^[7]. The DNA is then threaded through the central pore of XPD helicase, which then opens up the double helix.

Disease

Mutations in XPD helicase are associated with three distinct diseases: Cockayne Syndrome (CS), Xeroderma Pigmentosum (XP), and trichothiodystrophy (TTD) ^[8]. The common symptom between these diseases is sensitivity to UV light because of defects in the repair system that fixes mutations caused by UV radiation ^[2]. CS is characterized by short stature, signs of premature aging, failure to gain weight, impaired development of the nervous system, and photosensitivity ^[9]. XP is characterized by extreme sensitivity to sunlight and a higher risk of skin cancer . TTD is characterized by sparse and brittle hair, pregnancy-induced high blood pressure, intellectual disabilities, a higher risk of recurrent respiratory infections, and photosensitivity ^[10]. Interestingly, only XP has been found to be associated with an increased risk of skin cancer; studies are being conducted to determine why some mutations in XPD helicase result in a higher risk of skin cancer and others do not.

Structure Description

Residues 7-283 form the Helicase ATP binding domain. Interaction with the gene MMS19 is mediated by region consisting of residues 438-637. Residues 234-237 form the motif which is the DEAH box of this transcription factor. A second motif located at residues 682-695 is where the nuclear localization signal is located. Iron Sulfur bonding residues consist of C116, C134, C155, and C160. Features of Cockayne Syndrome and Xeroderma pigmentosum have been associated with point mutation G602D, and point mutation L461V is associated with TTD1 ^[11].

Structural highlights

References

1. ↑ Mydlikova Z, Gursky J, Pirsel M. Transcription factor IIH - the protein complex with multiple functions. Neoplasma. 2010;57(4):287-90. PMID:20429618
2. ↑ ^{2.0 2.1 2.2} Fan L, Fuss JO, Cheng QJ, Arvai AS, Hammel M, Roberts VA, Cooper PK, Tainer JA. XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations. Cell. 2008 May 30;133(5):789-800. PMID:18510924 doi:10.1016/j.cell.2008.04.030
3. ↑ Tuteja N, Tuteja R. Unraveling DNA helicases. Motif, structure, mechanism and function. Eur J Biochem. 2004 May;271(10):1849-63. PMID:15128295 doi:http://dx.doi.org/10.1111/j.1432-1033.2004.04094.x
4. ↑ Vink AA, Roza L. Biological consequences of cyclobutane pyrimidine dimers. J Photochem Photobiol B. 2001 Dec 31;65(2-3):101-4. PMID:11809365
5. ↑ Buechner CN, Heil K, Michels G, Carell T, Kisker C, Tessmer I. Strand-specific recognition of DNA damages by XPD provides insights into nucleotide excision repair substrate versatility. J Biol Chem. 2014 Feb 7;289(6):3613-24. doi: 10.1074/jbc.M113.523001. Epub 2013, Dec 14. PMID:24338567 doi:http://dx.doi.org/10.1074/jbc.M113.523001
6. ↑ Kuper J, Braun C, Elias A, Michels G, Sauer F, Schmitt DR, Poterszman A, Egly JM, Kisker C. In TFIIH, XPD helicase is exclusively devoted to DNA repair. PLoS Biol. 2014 Sep 30;12(9):e1001954. doi: 10.1371/journal.pbio.1001954., eCollection 2014 Sep. PMID:25268380 doi:http://dx.doi.org/10.1371/journal.pbio.1001954
7. ↑ Constantinescu-Aruxandei D, Petrovic-Stojanovska B, Penedo JC, White MF, Naismith JH. Mechanism of DNA loading by the DNA repair helicase XPD. Nucleic Acids Res. 2016 Feb 20. pii: gkw102. PMID:26896802 doi:http://dx.doi.org/10.1093/nar/gkw102
8. ↑ Liu J, Fang H, Chi Z, Wu Z, Wei D, Mo D, Niu K, Balajee AS, Hei TK, Nie L, Zhao Y. XPD localizes in mitochondria and protects the mitochondrial genome from oxidative DNA damage. Nucleic Acids Res. 2015 Jun 23;43(11):5476-88. doi: 10.1093/nar/gkv472. Epub 2015, May 12. PMID:25969448 doi:http://dx.doi.org/10.1093/nar/gkv472
9. ↑ Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet. 1992 Jan 1;42(1):68-84. PMID:1308368 doi:http://dx.doi.org/10.1002/ajmg.1320420115
10. ↑ Hashimoto S, Egly JM. Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH. Hum Mol Genet. 2009 Oct 15;18(R2):R224-30. doi: 10.1093/hmg/ddp390. PMID:19808800 doi:http://dx.doi.org/10.1093/hmg/ddp390
11. ↑ . UniProt: a hub for protein information. Nucleic Acids Res. 2015 Jan;43(Database issue):D204-12. doi: 10.1093/nar/gku989. , Epub 2014 Oct 27. PMID:25348405 doi:http://dx.doi.org/10.1093/nar/gku989