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From Proteopedia
A NUCLEOTIDE-FLIPPING MECHANISM FROM THE STRUCTURE OF HUMAN URACIL-DNA GLYCOSYLASE BOUND TO DNA
Structural highlights
Disease[UNG_HUMAN] Defects in UNG are a cause of immunodeficiency with hyper-IgM type 5 (HIGM5) [MIM:608106]. A rare immunodeficiency syndrome characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE. It results in a profound susceptibility to bacterial infections.[1] [2] Function[UNG_HUMAN] Excises uracil residues from the DNA which can arise as a result of misincorporation of dUMP residues by DNA polymerase or due to deamination of cytosine. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
IntroductionGlycosylase is an enzyme. Its main function is in Base Excision Repair(BER). Base Excision Repair is a DNA repair mechanism that fixes the most common type of DNA damage. BER removes and repairs damaged bases usually these are single-stranded DNA breaks. BER corrects DNA damage that results from small leisures that do not disrupt the double helix[3]. FunctionGlycosylase does this by cleaving the glycosidic bond of the damaged nucleotide, leaving the Deoxyribose nucleotide with no base. The deoxyribose is then cleaved by AP endonuclease creating an AP site. The gap that is left is filled in through DNA Polymerase and DNA ligase[4]. Uracil-DNA GlycosylaseThe structure of Glycosylase has a couple of different forms in terms of its general structure there is Adenine and Uracil Glycosylase. DNA Uracil-Glycosylase specifically looks for any Uracil in the double-stranded DNA. It looks for Uracil in dsDNA because uracil is only found in ssDNA. So if a Uracil is found in dsDNA then that means the strand has been damaged and needs repair. When Uracil-DNA Glycosylase finds the site it binds to it. The of Uracil Glycosylase; D145, Y147, F158, N204, H268, L272 is what binds to the double-stranded DNA with the damaged lesion. Then a nucleotide-flipping mechanism flips the site of repair out of the double helix. The dsDNA has a 10bp that contains a U G base pair mismatch. This is what allows the and flip the damaged site out of the double helix. When flipped out of the helix takes its place in the minor groove since AP sites can be mutagenic[5]. The Uracil is then replaced with a Thymine. This is because Uracil and Thymine have identical base pairing properties. Thymine happens to have greater resistance to photochemical mutations which is why we see it in dsDNA and not Uracil.
A nucleotide-flipping mechanism from the structure of human uracil-DNA glycosylase bound to DNA., Slupphaug G, Mol CD, Kavli B, Arvai AS, Krokan HE, Tainer JA Nature. 1996 Nov 7;384(6604):87-92. PMID:8900285[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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