Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA.
Commun Biol. 2024 Nov 10;7(1):1482. doi: 10.1038/s42003-024-07179-1.
Fuchs Endothelial Corneal Dystrophy (FECD) is an aging disorder characterized by expedited loss of corneal endothelial cells (CEnCs) and heightened DNA damage compared to normal CEnCs. We previously established that ultraviolet-A (UVA) light causes DNA damage and leads to FECD phenotype in a non-genetic mouse model. Here, we demonstrate that acute treatment with chemical stressor, menadione, or physiological stressors, UVA, and catechol estrogen (4-OHE), results in an early and increased activation of ATM-mediated DNA damage response in FECD compared to normal CEnCs. Acute stress with UVA and 4OHE causes (i) greater cell-cycle arrest and DNA repair in G2/M phase, and (ii) greater cytoprotective senescence in NQO1 compared to NQO1 cells, which was reversed upon ATM inhibition. Chronic stress with UVA and 4OHE results in ATM-driven cell-cycle arrest in G0/G1 phase, reduced DNA repair, and cytotoxic senescence, due to sustained damage. Likewise, UVA-induced cell-cycle reentry, gamma-H2AX foci, and senescence-associated heterochromatin were reduced in Atm-null mice. Remarkably, inhibiting ATM activation with KU-55933 restored DNA repair in G2/M phase and attenuated senescence in chronic cellular model of FECD lacking NQO1. This study provides insights into understanding the pivotal role of ATM in regulating cell-cycle, DNA repair, and senescence, in oxidative-stress disorders like FECD.
福克司角膜内皮营养不良（FECD）是一种与年龄相关的疾病，其特征是角膜内皮细胞（CEnCs）快速丧失，且与正常 CEnCs 相比，DNA 损伤程度更高。我们之前已经证实，长波紫外线（UVA）会导致 DNA 损伤，并在非遗传的小鼠模型中引发 FECD 表型。在此，我们证明与正常 CEnCs 相比，化学应激物甲萘醌（menadione）或生理应激物 UVA 和儿茶酚雌激素（4-OHE）的急性处理会导致 FECD 中 ATM 介导的 DNA 损伤反应更早且更强烈地激活。UVA 和 4OHE 的急性应激导致：（i）G2/M 期的细胞周期停滞和 DNA 修复增加；（ii）与 NQO1 细胞相比，NQO1 中的细胞保护性衰老增加，而 ATM 抑制可逆转这种情况。UVA 和 4OHE 的慢性应激会导致 ATM 驱动的 G0/G1 期细胞周期停滞、DNA 修复减少和细胞毒性衰老，这是由于持续的损伤。同样，在 Atm 基因缺失的小鼠中，UVA 诱导的细胞周期再进入、γ-H2AX 焦点和衰老相关异染色质减少。值得注意的是，用 KU-55933 抑制 ATM 激活可恢复 G2/M 期的 DNA 修复，并减弱缺乏 NQO1 的 FECD 慢性细胞模型中的衰老。本研究为理解 ATM 在调节细胞周期、DNA 修复和衰老方面在 FECD 等氧化应激疾病中的关键作用提供了新的见解。
