XPD Helicase (3CRV)
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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 <ref name="Mydikova">PMID: 20429618</ref>. XPD helicase helps to stabilize the structure of TFIIH but also plays a functional role in repairing DNA as a helicase enzyme <ref name="Lifuss">PMID: 18510924 </ref>. 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 <ref name="Tuteja">PMID: 15128295 </ref>. 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 <ref name="Vink">PMID: 11809365 </ref>. 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) <ref name="Lifuss">PMID: 18510924 </ref>. This is the type of DNA repair that TFIIH, with the help of the XPD helicase subunit, carries out to remove the damaged DNA. | 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 <ref name="Mydikova">PMID: 20429618</ref>. XPD helicase helps to stabilize the structure of TFIIH but also plays a functional role in repairing DNA as a helicase enzyme <ref name="Lifuss">PMID: 18510924 </ref>. 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 <ref name="Tuteja">PMID: 15128295 </ref>. 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 <ref name="Vink">PMID: 11809365 </ref>. 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) <ref name="Lifuss">PMID: 18510924 </ref>. 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 <ref name="Buechner">PMID: 24338567 </ref>. The ATP-dependent helicase activity of XPD helicase, however, is only required for NER, even though TFIIH participates in both repair and transcription initiation <ref name="Kuper">PMID: 25268380 </ref>. XPD helicase not only unravels the DNA around the damage but also helps TFIIH in recognizing bulky lesions in DNA <ref > | + | Breaking the hydrogen bonds that hold the two DNA strands together requires energy, so XPD helicase is dependent on ATP <ref name="Buechner">PMID: 24338567 </ref>. The ATP-dependent helicase activity of XPD helicase, however, is only required for NER, even though TFIIH participates in both repair and transcription initiation <ref name="Kuper">PMID: 25268380 </ref>. XPD helicase not only unravels the DNA around the damage but also helps TFIIH in recognizing bulky lesions in DNA <ref>DOI 10.1093/nar/gkw102 </ref>. The DNA is then threaded through the central pore of XPD helicase, which then opens up the double helix. |
== Disease == | == Disease == | ||
| - | Mutations in XPD helicase are associated with three distinct diseases: Cockayne Syndrome (CS), Xeroderma Pigmentosum (XP), and trichothiodystrophy (TTD) <ref > | + | Mutations in XPD helicase are associated with three distinct diseases: Cockayne Syndrome (CS), Xeroderma Pigmentosum (XP), and trichothiodystrophy (TTD) <ref>DOI 10.1093/nar/gkw102 </ref>. 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 <ref name="Lifuss">PMID: 18510924 </ref>. |
CS is characterized by short stature, signs of premature aging, failure to gain weight, impaired development of the nervous system, and photosensitivity <ref name="Nance">PMID: 1308368 </ref>. 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 <ref name="Hashimoto">PMID: 19808800 </ref>. 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. | CS is characterized by short stature, signs of premature aging, failure to gain weight, impaired development of the nervous system, and photosensitivity <ref name="Nance">PMID: 1308368 </ref>. 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 <ref name="Hashimoto">PMID: 19808800 </ref>. 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. | ||
Revision as of 20:35, 24 April 2016
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