FOXO3a acts to suppress DNA double‐strand break‐induced mutations. Issue 9 (28th July 2020)

• Record Type: Journal Article
• Authors: White, Ryan R.; Maslov, Alexander Y.; Lee, Moonsook; Wilner, Samantha E.; Levy, Matthew; Vijg, Jan
• Is Part Of: Aging cell. Volume 19:Issue 9(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-07-28
• Subjects: aging -- bleomycin -- DNA damage -- DSB repair -- FOXO3a -- mutations; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13184
• Languages: English
• ISSNs: 1474-9718

Abstract

Abstract: 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. Abstract : 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.