XPD Helicase (3CRV)
From Proteopedia
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XPD HelicaseXeroderma pigmentosum group D (XPD) helicase is a subunit of Transcription Factor IIH (TFIIH), which aids in transcription initiation and 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. FunctionXPD helicase is an essential subunit, of the general transcription factor IIH (TFIIH), which is a complex that, along with other general transcription factors, helps 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. DiseaseThe NER pathway consists of 28 genes, three of which are part of TFIIH, and mutations in many of these are associated with a set of diseases that are similar but marked differences [8]. Mutations in XPD helicase are associated with three distinct diseases: Cockayne Syndrome (CS), Xeroderma Pigmentosum (XP), and trichothiodystrophy (TTD) [9]. 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 [10]. XP is characterized by extreme sensitivity to sunlight and a higher risk of skin cancer. Some XP patients have neurological degeneration. This is possibly due to the fact that neurons do not divide, and mutations that are not corrected by NER accumulate and eventually lead to cell death [8]. TTD is characterized by sparse and brittle hair, pregnancy-induced high blood pressure, intellectual disabilities, a higher risk of recurrent respiratory infections, and photosensitivity [11]. It has been proposed that specific mutations in XPD helicase affect the transcription activities of TFIIH more than its repair activities, resulting in development issues that lead to intellectual disabilities [8]. 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. Different types of mutations in XPD helicase as well as interactions between XPD helicase defects and defects in other NER proteins can result in these different diseases. Due to the complexity of these interactions, little is known about the molecular basis for the differences in these diseases [8]. Structure DescriptionThe structure of the subunit XPD helicase contains one main domain, a DNA interaction interface, and two motifs, one of which performs the function of unwinding the DNA strand. Residues 7-283 form the Helicase ATP binding domain(), where ATP itself binds at residues 42-49, (). 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 which is where the unwinding of DNA is performed (). 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 [12]. Structural highlights
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Matt Kohler, Bashir Noor, Chih Hao Huang, Michal Harel, Mark Heslin, Shane Devlin
