FOXO3a acts to suppress DNA double-strand break-induced mutations.
FOXO3a acts to suppress DNA double-strand break-induced mutations.
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DOI：
10.1111/acel.13184
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发表时间：
2020-09
期刊：
影响因子：
7.8
通讯作者：
Vijg J
中科院分区：
文献类型：
--
作者：
White RR;Maslov AY;Lee M;Wilner SE;Levy M;Vijg J
基因组的不稳定性是衰老的标志之一，DNA损伤和突变都被发现随着年龄的增长而在不同的物种中积累。某些基因家族，如sirtuins和FoxO家族的转录因子，已被证明在寿命延长中发挥作用。然而，与这些基因相关的长寿增加的潜在机制在很大程度上仍然未知，可能涉及对细胞应激源（如DNA损伤）的反应的调节。在这里，我们报告说，FOXO 3a降低了培养的小鼠胚胎成纤维细胞（MEF）的基因组不稳定性，这些细胞用诱导DNA双链断裂（DSB）的试剂（即，染色体断裂剂）处理。我们发现，DSB处理的原代人类和小鼠成纤维细胞上调FOXO 3a的表达。携带突变报告基因lacZ的MEFs中的FOXO 3a消融导致博莱霉素治疗后基因组重排增加;相反，发现人FOXO 3a的过表达抑制博莱霉素引起的突变积累。我们还表明，FOXO 3a在人原代成纤维细胞中的过表达减少了DSB诱导的γ H2 AX灶。在mES细胞中敲除FOXO 3a增加了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，FOXO 3a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。与衰老的保守途径相关的基因家族，如sirtuins和FoxOs，已被证明可以增强DNA修复。我们发现DNA双链断裂上调细胞中FOXO 3A的表达，FOXO 3A能够抑制致突变基因组重排。
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. Gene families associated with conserved pathways of aging, such as sirtuins and FoxOs, have been shown to act to enhance DNA repair. We show that DNA double‐strand breaks upregulate expression of FOXO3A in cells and that FOXO3A is capable of suppressing mutagenic genome rearrangements.
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小鼠肝脏中DNA双链断裂的受控诱导会诱导组织衰老的特征。
影响因子：
16.6
作者：
White, Ryan R.;Milholland, Brandon;de Bruin, Alain;Curran, Samuel;Laberge, Remi-Martin;van Steeg, Harry;Campisi, Judith;Maslov, Alexander Y.;Vijg, Jan
通讯作者：
Vijg, Jan
影响因子：
56.9
作者：
Tran, H;Brunet, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1073/pnas.1216824110
发表时间：
2013-04-02
影响因子：
11.1
作者：
Kass, Elizabeth M.;Helgadottir, Hildur R.;Jasin, Maria
通讯作者：
Jasin, Maria
DOI：
10.1093/gerona/glu166
发表时间：
2015-01-01
影响因子：
5.1
作者：
Broer, Linda;Buchman, Aron S.;Murabito, Joanne M.
通讯作者：
Murabito, Joanne M.
影响因子：
56.9
作者：
Brunet, A;Sweeney, LB;Greenberg, ME
通讯作者：
Greenberg, ME