DNA Repair Section, National Institute on Aging, Baltimore, MD 21224, USA; Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
DNA Repair Section, National Institute on Aging, Baltimore, MD 21224, USA.
Neurobiol Dis. 2023 May;180:106092. doi: 10.1016/j.nbd.2023.106092. Epub 2023 Mar 21.
RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biochemical and biological roles of RecQ helicases are rather well established, however, there is no systematic study comparing the behavioral changes among various RecQ-deficient mice including consequences of exposure to DNA damage. Here, we investigated the effects of ionizing irradiation (IR) on three RecQ-deficient mouse models (RecQ1, WRN and RecQ4). We find abnormal cognitive behavior in RecQ-deficient mice in the absence of IR. Interestingly, RecQ dysfunction impairs social ability and induces depressive-like behavior in mice after a single exposure to IR, suggesting that RecQ proteins play roles in mood and cognition behavior. Further, transcriptomic and metabolomic analyses revealed significant alterations in RecQ-deficient mice, especially after IR exposure. In particular, pathways related to neuronal and microglial functions, DNA damage repair, cell cycle, and reactive oxygen responses were downregulated in the RecQ4 and WRN mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our findings suggest that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing a potential therapeutic target.
RecQ 解旋酶家族蛋白在维持基因组稳定性方面发挥着重要作用，包括 DNA 复制、重组和 DNA 修复。在人类细胞中，有五种 RecQ 解旋酶：RECQL1、Bloom 综合征 (BLM)、Werner 综合征 (WRN)、RECQL4 和 RECQL5。RecQ 蛋白功能障碍或缺失与遗传疾病、肿瘤发生、早衰和神经退行性变有关。RecQ 解旋酶的生化和生物学作用已经得到了很好的确立，然而，目前还没有系统的研究比较各种 RecQ 缺陷型小鼠的行为变化，包括暴露于 DNA 损伤后的后果。在这里，我们研究了电离辐射 (IR) 对三种 RecQ 缺陷型小鼠模型 (RecQ1、WRN 和 RecQ4) 的影响。我们发现，在没有 IR 的情况下，RecQ 缺陷型小鼠表现出异常的认知行为。有趣的是，RecQ 功能障碍会损害小鼠的社交能力，并在单次 IR 暴露后引起抑郁样行为，表明 RecQ 蛋白在情绪和认知行为中发挥作用。此外，转录组和代谢组学分析显示，RecQ 缺陷型小鼠，尤其是在暴露于 IR 后，发生了显著变化。特别是，与神经元和小胶质细胞功能、DNA 损伤修复、细胞周期和活性氧反应相关的途径在 RecQ4 和 WRN 小鼠中下调。此外，在 RecQ 缺陷型小鼠中发现了增加的 DNA 损伤反应。值得注意的是，在 RecQ 缺陷型小鼠中，有两个基因，醛缩酶果糖-1,6-二磷酸 B (Aldob) 和 NADPH 氧化酶 4 (Nox4)，表达水平不同。我们的研究结果表明，RecQ 功能障碍导致小鼠出现社交和抑郁样行为，而醛缩酶活性可能与这些变化有关，代表了一个潜在的治疗靶点。
