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MicroRNA binding mediated Functional sequence variant in 3'-UTR of DNA repair Gene XPC in Age-related Cataract.

ABSTRACT: DNA oxidative damage repair is strongly involved in the pathogenesis of age-related cataract (ARC). The sequence variants of in coding region of DNA repair genes have been shown to be associated with ARC. It is known that single nucleotide polymorphisms (SNPs) in the 3'-terminal untranslated region (3'-UTR) can alter the gene expression by binding with microRNAs (miRNAs). We hypothesize that SNP(s) in miRNA binding site of certain DNA oxidative damage repair genes might associate with ARC risk. We examined 10 miRNA binding SNPs in 3'-UTR of 7 oxidative damage genes and revealed the XPC- rs2229090 C allele was associated with nuclear type of ARC (ARNC) risk in Chinese population. The individuals with the variant G allele (CG and GG) of XPC- rs2229090 had higher XPC mRNA expression compared to individuals carrying CC genotype. The in vitro assay showed that luciferase reporter gene expression can be down regulated by hsa-miR-589-5p in cells transfected with rs2229090 C allele compared to G allele. These results suggested that the C allele of XPC-2229090 increase the risk with ARNC. The mechanism underlying might be due to the stronger interation of the C allele with hsa-miR-589-5p, resulting in lower XPC expression and DNA repair capability than the individuals carring G allele in lens.

SUBMITTER: Zou X

PROVIDER: S-EPMC6185952 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Project description:Nucleotide excision repair (NER) excises a variety of environmentally derived DNA lesions. However, NER efficiencies for structurally different DNA lesions can vary by orders of magnitude; yet the origin of this variance is poorly understood. Our goal is to develop computational strategies that predict and identify the most hazardous, repair-resistant lesions from the plethora of such adducts. In the present work, we are focusing on lesion recognition by the xeroderma pigmentosum C protein complex (XPC), the first and required step for the subsequent assembly of factors needed to produce successful NER. We have performed molecular dynamics simulations to characterize the initial binding of Rad4, the yeast orthologue of human XPC, to a library of 10 different lesion-containing DNA duplexes derived from environmental carcinogens. These vary in lesion chemical structures and conformations in duplex DNA and exhibit a wide range of relative NER efficiencies from repair resistant to highly susceptible. We have determined a promising set of structural descriptors that characterize initial binding of Rad4 to lesions that are resistant to NER. Key initial binding requirements for successful recognition are absent in the repair-resistant cases: There is little or no duplex unwinding, very limited interaction between the β-hairpin domain 2 of Rad4 and the minor groove of the lesion-containing duplex, and no conformational capture of a base on the lesion partner strand. By contrast, these key binding features are present to different degrees in NER susceptible lesions and correlate to their relative NER efficiencies. Furthermore, we have gained molecular understanding of Rad4 initial binding as determined by the lesion structures in duplex DNA and how the initial binding relates to the repair efficiencies. The development of a computational strategy for identifying NER-resistant lesions is grounded in this molecular understanding of the lesion recognition mechanism.

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MicroRNA binding mediated Functional sequence variant in 3'-UTR of DNA repair Gene XPC in Age-related Cataract.

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