DNA Damage in Lens Epithelial Cells and Peripheral Lymphocytes from Age-Related Cataract Patients

Zhang, Junfang; Wu, Jian; Yang, Ling; Zhu, Rongrong; Yang, Mei; Qin, Bai; Shi, Huidong; Guan, Huaijin

doi:10.1159/000356399

Cited by 21 publications

(22 citation statements)

References 26 publications

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“…Individuals with different genotypes showed various damage levels in their peripheral lymphocytes (41). Moreover, DNA damage in LECs was correlated to that in peripheral lymphocytes (33). This study had similar results.…”

Section: Discussionsupporting

confidence: 77%

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A variant in a microRNA binding site in NEIL2 3′UTR confers susceptibility to age‐related cataracts

et al. 2019

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DNA damage in lens cells is considered a critical trigger for the onset of age‐related cataracts (ARCs). Among DNA repair pathways, the base excision repair (BER) pathway is responsible for mending single‐strand breaks in DNA. In this case‐control study with 993 ARC cases and 993 healthy controls, we genotyped 9 single‐nucleotide polymorphisms (SNPs) within microRNA (miRNA) regions of 6 BER pathway genes and examined their associations with ARC susceptibility. We identified rs4639:T > C in the Nei‐like DNA glycosylase 2 (NEIL2) gene as significantly associated with ARCs. Individuals carrying different rs4639 alleles had distinct NEIL2 expression in lens capsule tissues from ARC cases and controls. Bioinformatics predicts that the rs4639 T allele could disrupt hsa‐miR‐3912‐5p binding. The results of the luciferase reporter assay were in concordance with this prediction. This study has added more evidence that SNP‐modified posttranscriptional gene regulation by miRNA might be a potential pathogenic mechanism of ARCs. SNPs potentially affecting miRNA binding to the 3′UTR of BER pathway genes could contribute to discrepant disease susceptibility. NEIL2‐rs4639T was strongly associated with a protective role in ARCs. This protective role might be fulfilled by maintaining normal expression of NEIL2 in the mediation of disrupted binding of rs4639T with hsa‐miR‐3912‐5p. A further study to generate model systems (cell lines or animal models) with NEIL2 variants is warranted. The results provide 2 molecular targets (e.g., NEIL2 and hsa‐miR‐3912‐5p) for intervention strategies of ARC in the future.—Kang, L., Zou, X., Zhang, G., Xiang, J., Wang, Y., Yang, M., Chen, X., Wu, J., Guan, H. A variant in a microRNA binding site in NEIL23′UTR confers susceptibility to age‐related cataract. FASEB J. 33, 10469–10476 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 77%

“…LECs and lymphocytes were isolated and suspended in PBS at 1 3 10 4 cells/ml. The data analysis was performed by measuring the percentage of DNA in the tail of comets (%tail DNA) and the olive tail moment (OTM) according to a previously described method (33).…”

Section: Snp Genotypingmentioning

confidence: 99%

A variant in a microRNA binding site in NEIL2 3′UTR confers susceptibility to age‐related cataracts

et al. 2019

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“…The modified Comet assay for lymphocytes and data analysis was carried out according to the method described by Zhang et al. ().…”

Section: Methodsmentioning

confidence: 99%

Functional SNP in 3′-UTR MicroRNA-Binding Site ofZNF350Confers Risk for Age-Related Cataract

Ren

Zhang

et al. 2016

Human Mutation

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Many studies have suggested that individual susceptibility to age-related cataract (ARC) may be associated with DNA sequence polymorphisms affecting gene regulation. As DNA repair is implicated in ARC pathogenesis and single-nucleotide polymorphisms (SNPs) in the 3'-terminal untranslated region (3'-UTR) targeted by microRNAs (miRNAs) can alter the gene function, we hypothesize that the miRNA-binding SNPs (miRSNPs) in DNA double-strand break repair (DSBR) and nucleotide excision repair (NER) pathways might associate with ARC risk. We genotyped nine miRSNPs of eight genes in DSBR and NER pathways in Chinese population and found that ZNF350- rs2278414:G>A was significantly associated with ARC risk. Even though the Comet assay of cellular DNA damage indicated that all the subtypes of ARC patients had more DNA breaks in peripheral lymphocytes than the controls independent of rs2278414 genotypes, individuals carrying the variant A allele (AA and AG) had lower ZNF350 mRNA levels compared with individuals with GG genotype. Moreover, the in vitro experiment indicated that miR-21-3p and miR-150-5p specifically downregulated luciferase reporter expression in the cell lines transfected with rs2278414 A allele compared with rs2278414 G. These results suggested that the association of SNP rs2278414 with ARC might involve an altered miRNA regulation of ZNF350.

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“…Epithelia removed from the lenses of cataract patients prior to surgery showed a higher level of DNA damage (strand breaks) compared to similar tissue from human donor eyes, and the damage was significantly greater in cortical cataracts compared to nuclear and posterior subcapsular opacities (24). A similar investigation found increased amounts of DNA strand breaks present in lens epithelial cells and lymphocytes of patients with cortical, nuclear and posterior subcapsular cataracts, compared to controls (25). Results of earlier studies had suggested that genotoxic damage may be associated with the development of certain types of human cataracts (26,27).…”

Section: Introductionmentioning

confidence: 81%

PARP‐1/PAR Activity in Cultured Human Lens Epithelial Cells Exposed to Two Levels of UVB Light

Cencer

Chintala

Townsend

et al. 2017

Photochem & Photobiology

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This study investigated poly(ADP-ribose) polymerase-1 (PARP-1) activation in cultured human lens epithelial cells exposed to two levels of UVB light (312 nm peak wavelength), 0.014 and 0.14 J cm À2 ("low" and "high" dose, respectively). At the low dose, PARP-1 and poly(ADP-ribose) (PAR) polymers acted to repair DNA strand breaks rapidly with no subsequent major effects on either cell morphology or viability. However, following the high UVB dose, there was a dramatic second phase of PARP-1 activation, 90 min later, which included a sudden reappearance of DNA strand breaks, bursts of reactive oxygen species (ROS) formation within both the mitochondria and nucleus, a translocation of PAR from the nucleus to the mitochondria and an ultimate 70% loss of cell viability occurring after 24 h. The results provide evidence for an important role for PARP-1 in protecting the human lens epithelium against low levels of UVB light, and possibly participating in the triggering of cell death following exposure to toxic levels of radiation.

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DNA Damage in Lens Epithelial Cells and Peripheral Lymphocytes from Age-Related Cataract Patients

Cited by 21 publications

References 26 publications

A variant in a microRNA binding site in NEIL2 3′UTR confers susceptibility to age‐related cataracts

A variant in a microRNA binding site in NEIL2 3′UTR confers susceptibility to age‐related cataracts

Functional SNP in 3′-UTR MicroRNA-Binding Site ofZNF350Confers Risk for Age-Related Cataract

PARP‐1/PAR Activity in Cultured Human Lens Epithelial Cells Exposed to Two Levels of UVB Light

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