Research Paper Volume 13, Issue 4 pp 5383—5402
CircMRE11A_013 binds to UBXN1 and integrates ATM activation enhancing lens epithelial cells senescence in age-related cataract
- 1 Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- 2 Department of Ophthalmology, The Third People’s Hospital of Changzhou, Jiangsu, China
Received: June 9, 2020 Accepted: December 14, 2020 Published: January 28, 2021https://doi.org/10.18632/aging.202470
How to Cite
Copyright: © 2021 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Ultraviolet B (UVB) irradiation could trigger DNA double-strand breaks (DDSBs) and senescence in lens epithelial cells (LECs), thus inducing age-related cortical cataract (ARCC) formation. Cell-cycle irreversible arrest induced by DDSBs depended on excessive activation of ataxia-telangiectasia mutated kinase (ATM). We studied the up-regulated circular RNA circMRE11A_013 (circMRE11A) in LECs of ARCC and SRA01/04 cell lines under UVB exposure. In vitro, knockdown of circMRE11A in SRA01/04 cell lines enhanced cell viability and cell cycle, while over-expression of circMRE11A exhibited an opposite trend. Additionally, circMRE11A could bind to UBX domain-containing protein 1 (UBXN1), which might enhance excessive activation of ATM and initiate ATM/p53/p21 signaling pathway causing LECs cell-cycle arrest and senescence. In vivo, recombinant adeno-associated virus vectors (rAAV-2) virions of circMRE11A (circMRE11A-AAV2) was injected to Institute of Cancer Research mouse vitreous cavity. The circMRE11A-AAV2 could express in mouse lens at 4 weeks. The LECs aging and opacity lens were observed at 8 weeks after the injection. Together, our findings reveal a previously unidentified role of circMRE11A interacting with UBXN1 in enhancing ATM activity and inhibiting LECs cell-cycle in ARCC formation. The findings might give us a better understanding of ARC pathology and provide a novel and more effective therapeutic approaches for ARC treatment.
UVB: Ultraviolet B; DDSBs: DNA double-strand breaks; LECs: lens epithelial cells; ARC: age-related cataract; ARCC: age-related cortical cataract; CircRNAs: circular RNAs; miRNAs: microRNAs; ATM: ataxia-telangiectasia; PTMs: post-translational modifications; RT-qPCR: reverse transcription-quantitative; FISH: Fluorescence in situ hybridization; FCM: flow cytometry; UBXN1: UBX domain-containing protein 1; ICR: Institute of Cancer Research; rAAV: recombinant adeno-associated virus vectors; CircMRE11A-AAV2: recombinant adeno associated virus vectors rAAV-2 virions of circMRE11A; LOCS III: Lens Opacities Classification III; PI: Propidium iodide; NC: negative control; ANOVA: The one-way analysis of variance test; UBX: Ubiquitin regulatory X; MS: mass spectrometry.