FOXO3a acts to suppress DNA double-strand break-induced mutations.,Aging Cell

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FOXO3a acts to suppress DNA double-strand break-induced mutations.
Aging Cell ( IF 8.0 ) Pub Date : 2020-07-28 , DOI: 10.1111/acel.13184
Ryan R White ₁ , Alexander Y Maslov ₁ , Moonsook Lee ₁ , Samantha E Wilner ₂ , Matthew Levy ₂ , Jan Vijg _{1,

3}

Affiliation

Genomic instability is one of the hallmarks of aging, and both DNA damage and mutations have been found to accumulate with age in different species. Certain gene families, such as sirtuins and the FoxO family of transcription factors, have been shown to play a role in lifespan extension. However, the mechanism(s) underlying the increased longevity associated with these genes remains largely unknown and may involve the regulation of responses to cellular stressors, such as DNA damage. Here, we report that FOXO3a reduces genomic instability in cultured mouse embryonic fibroblasts (MEFs) treated with agents that induce DNA double‐strand breaks (DSBs), that is, clastogens. We show that DSB treatment of both primary human and mouse fibroblasts upregulates FOXO3a expression. FOXO3a ablation in MEFs harboring the mutational reporter gene lacZ resulted in an increase in genome rearrangements after bleomycin treatment; conversely, overexpression of human FOXO3a was found to suppress mutation accumulation in response to bleomycin. We also show that overexpression of FOXO3a in human primary fibroblasts decreases DSB‐induced γH2AX foci. Knocking out FOXO3a in mES cells increased the frequency of homologous recombination and non‐homologous end‐joining events. These results provide the first direct evidence that FOXO3a plays a role in suppressing genome instability, possibly by suppressing genome rearrangements.

中文翻译：

FOXO3a 可抑制 DNA 双链断裂诱导的突变。

基因组不稳定是衰老的标志之一，并且已发现不同物种的 DNA 损伤和突变会随着年龄的增长而积累。某些基因家族，例如去乙酰化酶和转录因子 FoxO 家族，已被证明在延长寿命方面发挥着作用。然而，与这些基因相关的延长寿命的机制仍然很大程度上未知，并且可能涉及对细胞应激源（例如 DNA 损伤）反应的调节。在这里，我们报告 FOXO3a 降低了用诱导 DNA 双链断裂 (DSB) 的试剂（即断裂剂）处理的培养的小鼠胚胎成纤维细胞 (MEF) 的基因组不稳定性。我们发现，对人类和小鼠原代成纤维细胞进行 DSB 处理后，FOXO3a 的表达上调。携带突变报告基因 lacZ 的 MEF 中的 FOXO3a 消融导致博来霉素治疗后基因组重排增加；相反，人类 FOXO3a 的过度表达被发现可以抑制博莱霉素引起的突变积累。我们还发现，人原代成纤维细胞中 FOXO3a 的过度表达会减少 DSB 诱导的 γH2AX 病灶。敲除 mES 细胞中的 FOXO3a 会增加同源重组和非同源末端连接事件的频率。这些结果提供了第一个直接证据，表明 FOXO3a 可能通过抑制基因组重排在抑制基因组不稳定性中发挥作用。

更新日期：2020-09-24

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