XPD Helicase (3CRV)

XPD Helicase

Xeroderma pigmentosum group D (XPD) is a subunit of Transcription Factor II Human (TFIIH).

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, these 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) (7). 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 (8). XP is characterized by extreme sensitivity to sunlight and a higher risk of skin cancer (9). 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.

Structural highlights

References

1. Mydilkova, Z., Gursky, J., Piersel, M. (2010) Transcription factor IIH- the protein complex with multiple functions, Neoplasm 57, 287-290.
2. Li, F., Fuss, J., Cheng, Q., Arvai, A., Hammel, M., Roberts, V., Cooper, P., Tainer, J. (2008) XPD helicase structures and activities: Insights into the cancer and aging phenotypes from XPD mutations, Cell 133, 789-800.
3. Tuteja, N., Tuteja, R. (2004) Unraveling DNA helicases: Motif, structure, mechanism and function, Eur J Biochem 271, 1849-1863.
4. Vink, A., Roza, L. (2001) Biological consequences of cyclobutane pyrimidine dimers, Journal of Photochemistry and Photobiology, 65, 101-104.
5. Buechner, C., Heil, K., Michels, G., Carell, T., Kisker, C., Tessmer, I. (2014) Strand-specific recognition of DNA damages by XPD provides insights into nucleotide excision repair substrate versatility, J Biol Chem, 289, 3613-3624.
6. Kuper, J., Braun, C., Elias, A., Michels, G., Sauer, F., Schmitt, D., Poterszman, A., Egly, J., Kisker., C. (2014) PLoS Biol., 12. doi: 10.1371/journal.pbio.1001954.
7. Constantinescu-Aruxandei, D., Petrovic-Stojanovska, B., Penedo, J., White, M., Naismith, J. (2016) Mechanism of DNA loading by the DNA repair helicase XPD, Nucl. Acids Res., 44, 2806-2815.
8. Nance MA, Berry SA. (1992) Cockayne syndrome: review of 140 cases, Am J Med Genet 42, 68-84. Review.
9. Hengge UR, Emmert S. (2008) Clinical features of xeroderma pigmentosum, Adv Exp Med Biol. 637, 10-8. Review.
10. Hashimoto S, Egly JM. (2009) Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH, Hum Mol Genet. 18, R224-30. doi: 10.1093/hmg/ddp390. Review.