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

Abstract

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

Development of a Custom NGS Panel for the Determination of Bladder Cancer Risk

“…In our study, we found that NEIL2 G/G genotype for rs4639 was associated with 0, 49-fold decreased risk of BCa. This inverse association could be explained by the fact that the minor allele interacts with some speci c miRNA, which activates the BER pathway [41]. Moreover, we have found that rs4639 and rs804276 in NEIL2 gene were in linkage disequilibrium (p-value = 0.03).…”

The Role of MicroRNA in DNA Damage Response

“…In addition to affecting PARP-1, miRNAs may also interfere with DNA SSBs in other way. Kang et al (2019) found that miR-3912-5p might bind to 3′-UTR of BER protein NEIL2, thereby affecting DNA damage in lens cells. And miR-590 slowed the proliferation and promoted the repair of SSBs in embryonic stem cells ( Liu et al, 2014 ), but the mechanism of which is still unclear.…”

A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase

“…The reported associations of polymorphisms in the non-coding parts of hNEIL2 include the following: risk of squamous cell oral and oropharynx carcinoma [22], testicular germ cell tumors [23], gastric cancer [24], cervical squamous cell carcinomas and intraepithelial neoplasias [25] and breast cancer [26], decreased progression-free survival in colorectal cancer patients [27], non-small cell lung cancer patients treated with cisplatin [28] and breast cancer [26], and recurrence in BCGtreated bladder cancer [29]. Also, non-coding hNEIL2 polymorphisms showed associations with addiction and behavioral disinhibition [30], susceptibility to age-related cataracts [31], and increased chromosome aberrations induced by tobacco nitrosamines [32]. Neil2 −/− mice are viable but show an increased production of pro-inflammatory cytokines upon bacterial infection or challenge with lipopolysaccharide [33][34][35].…”